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Advanced Technologies and Treatments for Diabetes

Immunomodulation
Immune intervention for type 1 diabetes mellitus
J. S. Skyler
Division of Endocrinology, Diabetes and Metabolism; and Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, USA

The major form of type 1 diabetes (T1D) is characterised by immune-mediated pancreatic islet b-cell destruction, and Correspomdence to:
Jay S. Skyler,
has also been called type 1A diabetes to distinguish it from idiopathic forms of islet b-cell loss. Since the first demon- Division of Endocrinology, Diabetes, and Metabolism; and
stration of islet cell antibodies in 1974, the concept has been that this form of diabetes is autoimmune in nature. The Diabetes Research Institute, University of Miami Miller School
commonly accepted concept is that antibodies (representing the humoral arm of the immune system) do not mediate of Medicine, Miami, FL, USA
Tel.: 305-243-6146
the b-cell destruction but rather serve as markers of that destruction, while the cellular arm of the immune system,
Fax: 305-243-4484
specifically T-lymphocytes, mediate the b-cell destruction. Yet, the T-lymphocytes do not act alone. They receive help in Email: jskyler@miami.edu
initiating the response from antigen-presenting cells such as dendritic cells and macrophages, and appear to receive
help also from B-lymphocytes. In addition, the initial immune response engenders secondary and tertiary responses – Disclosures:
JSS is Chairman of Type 1 Diabetes TrialNet, a clinical trials
involving the whole immunological army – which collectively result in impairment of b-cell function, progressive network conducting multiple studies designed to interrupt the
destruction of b-cells, and consequent development of type 1A diabetes. The process is insidious and may evolve over type 1 diabetes disease process. Also, recipient of grant
many years, with the overt expression of clinical symptoms becoming apparent only when most b-cells have been support from Bayhill Therapeutics and Osiris Therapeutics. The
author serves on the Board of Directors of Amylin
destroyed. Yet, the process clearly evolves at different speeds – much more rapidly in young children, much more Pharmaceuticals, and chairs the Type 1 Diabetes Advisory Board
slowly in older individuals. And, although it has been thought that ultimately there is complete b-cell destruction, sev- for sanofi-aventis.
eral studies have now demonstrated some degree of persistent b-cell function or existence (at autopsy) in long-stand-
Endorsed by the International Conference on ATTD organized
ing T1D. A major focus of investigation in T1D is the preservation of b-cell function (and, it is hoped, of b-cells
by Kenes International.
themselves), in the expectation that continuing endogenous insulin secretion will contribute towards better glycaemic
control, reduce episodes of severe hypoglycaemia, and slow the development of complications such as retinopathy and
nephropathy. Thus, there have been many studies designed to interdict the T1D disease process, mostly by altering the
immune system, both during the stage of evolution of the disease and at the time of disease onset. This chapter of
the Yearbook of Advanced Technology and Treatments in Diabetes reviews the key papers that have appeared in this
field between July 2009 and June 2010. Articles selected were confined to studies in human beings. All immune inter-
vention studies reported in this time frame were included. In addition, the author selected other relevant articles
dealing with mechanisms, markers, triggers, and pathology of human type 1 diabetes.

1
IMMUNE INTERVENTIONS Four-year metabolic outcome of Diabetes Research Center and University
Hospital, Brussels Free University-VUB,
STUDIES IN HUMAN TYPE 1 a randomised controlled CD3- Brussels, Belgium, 2Hospital München-
DIABETES antibody trial in recent-onset Schwabing, Munich, Germany, 3Department of
type 1 diabetic patients Endocrinology, Katolieke Universiteit Leuven-
The first group of papers involves reports of
KUL, Leuven, Belgium, 4Department of
immune intervention studies in human type 1 depends on their age and Biostatistics and Medical Informatics, Brussels
diabetes, mostly in recent-onset T1D. baseline residual b-cell mass Free University-VUB, Brussels, Belgium,
5
Hôpital Erasme, Université Libre de Bruxelles-
B. Keymeulen,1 M. Walter,2 C. Mathieu,3
ULB, Brussels, Belgium, 6Department of
L. Kaufman,4 F. Gorus,1 R. Hilbrands,1
Diabetology, University Hospital Antwerp,
E. Vandemeulebroucke,1 U. Van de Velde,1
Edegem, Belgium, 7INSERM U580-IRNEM,
L. Crenier,5 C. De Block,6 S. Candon,7
Hôpital Necker, Paris, France, and 8Sir William
H. Waldmann,8 A. G. Ziegler,2 L. Chatenoud,7
Dunn School of Pathology, Oxford, UK
D. Pipeleers1
Diabetologia 2010; 53: 614–23

ª 2011 Blackwell Publishing Ltd Int J Clin Pract, February 2011, 65 (Suppl. 170), 61–70 61
62 Immunomodulation

9
Background: The authors previously National Institute for Allergy Immunology and Cyclosporin and methotrexate
reported the results of their initial rando- Infectious Diseases, Bethesda, MD, USA, and
mised, controlled 18-month trial in which a 10
Immune Tolerance Network, Bethesda, MD,
therapy induces remission in
short course of the humanised Fc-mutated USA type 1 diabetes mellitus
recombinant aglycosylated anti-human CD3 Clin Immunol 2009; 132: 166–73
D. O. Sobel, A. Henzke, V. Abbassi
antibody, ChAglyCD3 (now called ote-
Department of Pediatrics, Georgetown Uni-
lixizumab), was given for six consecutive days Background: The authors previously versity Medical Center, Washington, DC, USA
shortly after diagnosis of T1D. In their earlier reported the 1- and 2-year results of an open- Acta Diabetol 2010; 47: 243–50
report, they demonstrated preservation of b- label trial in which a short course of the
cell function – as measured by C-peptide – humanised Fc-mutated CD3-specific mono-
and equivalent glycaemic control with lower Background: Studies reported in the late
clonal antibody, hOKT3c1 (Ala-Ala) (now
insulin doses. The current paper extends fol- 1980s and early 1990s had shown that cyclo-
called teplizumab), was given for 14 consecu-
low-up to 4 years. sporine appears to have beneficial effects in
tive days shortly after diagnosis of T1D. In
Methods: The original study included 80 recent-onset T1D, as long as treatment is
the reports of that study, they demonstrated
subjects (40 treated with anti-CD3, 40 treated maintained, but at the price of significant
preservation of b-cell function – as measured
with placebo), ages 12–39. Four-year follow- adverse effects, particularly induction of renal
by C-peptide – and both better glycaemic
up data are reported on 64 subjects (33 of the damage. The current study was designed as a
control and lower insulin doses. The current
anti-CD3 subjects, 31 of the placebo subjects). pilot study to determine whether lower doses
paper reports on a smaller second trial that
Change in insulin dose over 48 months was of cyclosporine could avert the adverse effects,
had enrolment interrupted due to adverse
the primary end-point. and if combined with methotrexate might still
events.
Results: Treatment with anti-CD3 delayed demonstrate the beneficial effects.
Methods: The study enrolled 10 subjects
the rise in insulin requirements of subjects Methods: The study was an open non-
before being halted for adverse events that
with recent-onset T1D and reduced the mag- randomised pilot study, in which seven
seemed to be a consequence of higher doses
nitude of that rise over 48 months of follow- subjects with recent-onset T1D were treated
of the drug used in this trial. The subjects
up. Using multivariate analysis, this effect was with cyclosporine plus methotrexate, and
were followed, nonetheless.
correlated with higher baseline b-cell function compared to 10 subjects not so treated. Only
Results: At 2 years, the treated subjects
and younger age. the clinical course was evaluated, and b-cell
(n = 6) had lower insulin doses than the
Conclusions: Anti-CD3 therapy shortly function was not reported.
comparison subjects (n = 4), and a trend
after onset of T1D has sustained effects for Results: During the 1 year of follow-up,
towards better maintained C-peptide. The C-
48 months. during which treatment was maintained in
peptide levels in the treated subjects remained
the intervention group, that group had
fairly constant between 2 and 5 years of fol-
lower insulin doses, greater likelihood of
low-up. The authors concluded that the
Treatment of patients with discontinuing insulin, and at the 12-month
higher doses resulted in more adverse events
new-onset type 1 diabetes with time point lower A1c. Adverse effects were
without increased efficacy.
said to be less than in earlier cyclosporine
a single course of anti-CD3 mAb Conclusion: This small study suggests that
studies.
anti-CD3 therapy shortly after onset of T1D
Teplizumab preserves insulin Conclusion: The combination of low-dose
may have prolonged effects with fairly con-
production for up to 5 years cyclosporine plus methotrexate may improve
stant C-peptide levels between 2 and 5 years.
the course of T1D over 1 year.
• Comment: These two studies demonstrate
K. C. Herold,1,2 S. Gitelman,3 C. Greenbaum,6 • Comment: This study attempts to take
that relatively short courses of treatment (6
J. Puck,3 W. Hagopian,7 P. Gottlieb,8 advantage of an oft utilised medical principle
or 14 days) with an anti-CD3 monoclonal
P. Sayre,10 P. Bianchine,9 E. Wong,4 that using lower doses of two drugs may
antibody can have sustained effects on b-cell
V. Seyfert-Margolis,10 K. Bourcier,10 obviate the adverse effects of higher doses,
function – as measured by C-peptide – for as
J. A. Bluestone,5,10 Group Immune Tolerance whilst still achieving efficacy. The study was a
long as 4 to 5 years. Both of the anti-CD3
Network ITN007AI Study very small pilot study in which only seven
1 antibodies used – otelixizumab and tep-
Department of Immunobiology, Yale Uni- subjects were treated. That small number
lizumab – are now being studied in full-scale
versity, New Haven, CT, USA, 2Department of makes it impossible to assess the risk of
phase 3 trials for potential commercialisation
Medicine, Yale University, New Haven, CT, adverse effects. Also, the absence of measure-
for use in recent-onset T1D. Thus, the fact
USA, 3Department of Pediatrics, University of ment of b-cell function makes it impossible
that there are long-term beneficial effects is
California at San Francisco, CA, USA, to compare the outcome with that in other
4 important. Nonetheless, in the original trials
Department of Statistics, University of Califor- contemporary studies. Finally, most current
with both of these antibodies, there was pro-
nia at San Francisco, CA; PPD Inc., Wilming- studies in recent-onset T1D do not intention-
gressive decline in b-cell function, suggesting
ton, NC, USA, 5Department of Medicine, ally attempt to reduce insulin doses to achieve
that there may be a need for repeated courses
University of California at San Francisco, CA, ‘remission’, but rather do so only to avert
of administration. Alternatively, the efficacy
USA, 6Benaroya Research Institute, Seattle, hypoglycaemia, maintaining the highest insu-
of these antibodies might be improved if used
WA, USA, 7Department of Medicine, Pacific lin dose that does not result in significant
in combination therapy with another agent
Northwest Research Institute and University of hypoglycaemia. This makes the claim of
(or agents) acting synergistically to improve
Washington, USA, 8Department of Medicine, achieving ‘remission’ because insulin was able
b-cell function.
University of Colorado, Denver, CO, USA, to be discontinued difficult to interpret.

ª 2011 Blackwell Publishing Ltd Int J Clin Pract, February 2011, 65 (Suppl. 170), 61–70
Immunomodulation 63

Failure to preserve b-cell decline in b-cell function in recent-onset T-lymphocyte mediated diseases, by serving as
T1D. antigen-presenting cells or generating cryptic
function with mycophenolate • Comment: This large, well-powered study peptides to which T-lymphocytes are not tol-
mofetil and daclizumab failed to demonstrate preservation of b-cell erant. This study used the anti-CD20 anti-
combined therapy in patients function in recent-onset T1D. Although body, rituximab, to selectively deplete
many interventions have shown benefit in B-lymphocytes in recent-onset T1D.
with new-onset type 1 diabetes recent-onset T1D, this study reminds us Methods: The study randomised 87 sub-
P. A. Gottlieb,1 S. Quinlan,2 H. Krause-Stein- that not all interventions which show prom- jects (57 assigned to anti-CD20, 30 assigned
rauf,2 C. J. Greenbaum,3 D. M. Wilson,4 ise in animal models will work in human to placebo), ages 8–45. Intervention consisted
H. Rodriguez,5 D. A. Schatz,6 A. M. Moran,7 beings. The study does represent one of the of four weekly infusions. The primary end-
J. M. Lachin,2 J. S. Skyler,8 Type 1 Diabetes first, if not the first, fully powered study point was b-cell function – as measured by
TrialNet MMF ⁄ DZB Study Group using combination therapy in recent-onset C-peptide – at 1 year, with 78 subjects
1 T1D. There will no doubt be other combi- included in the analysis.
Barbara Davis Center for Childhood Diabe-
tes, University of Colorado at Denver, Aurora, nation therapy trials. In designing them, Results: At 1 year, the mean level of C-
CO, USA, 2Biostatistics Center, George Wash- one might note one feature of this study – peptide was significantly higher in the ritux-
ington University, Rockville, MD, USA, 3Bena- half of the treated subjects received an infu- imab group than in the placebo group, and
roya Research Institute, Diabetes Clinical sion of DZB, and half of the placebo sub- declined at a slower rate. The rituximab
Research, Seattle, WA, USA, 4Pediatric Endo- jects received an infusion of DZB. This group also had significantly lower A1c levels
crinology Department, Stanford University, maintained masking, while not requiring all and required less insulin. Adverse effects were
Stanford, CA, USA, 5Department of Pediatrics, subjects to receive infusions. This is a minimal and mostly occurred during the first
Indiana University, Indianapolis, IN, USA, design that can be used if a single agent is rituximab infusion.
6 being compared to its use in combination. Conclusions: The anti-CD20 antibody rit-
Department of Pediatrics, University of
Florida, Gainesville, FL, USA, 7Department of Another approach would be a factorial uximab showed beneficial effects on b-cell
Pediatrics, University of Minnesota, design. Attention to design of combination function in recent-onset T1D, suggesting a
Minneapolis, MN, USA, and 8Diabetes studies will be an important consideration potential role for B-lymphocytes in T1D path-
Research Institute, University of Miami, Miami, in future T1D trials. ogenesis.
FL, USA • Comment: This study demonstrates that a
Diabetes Care 2010; 33: 826–32 relatively short course of treatment (weekly
Rituximab, B-lymphocyte infusions over 4 weeks) with an anti-CD20
Background: The authors evaluated the depletion, and preservation of monoclonal antibody can have beneficial
use of mycophenolate mofetil (MMF), either b-cell function effects on b-cell function – as measured by
alone or in combination with daclizumab C-peptide – at 1 year. Nonetheless, there is
(DZB), in recent-onset T1D. MMF has M. D. Pescovitz,1 C. J. Greenbaum,2 progressive decline in b-cell function, as in
potent cytostatic effects on lymphocytes, and H. Krause-Steinrauf,3 D. J. Becker,4 virtually all intervention trials in recent-onset
has been effective in other autoimmune dis- S. E. Gitelman,5 R. Goland,6 P. A. Gottlieb,7 T1D, again suggesting that there may be a
eases and in diabetic animal models. DZB is J. B. Marks,8 P. F. McGee,3 A. M. Moran,9 need for repeated courses of administration,
a humanised monoclonal antibody that P. Raskin,10 H. Rodriguez,1 D. A. Schatz,11 or, alternatively, for combination therapy with
binds to CD25, the a-subunit of the inter- D. Wherrett,12 D. M. Wilson,13 J. M. Lachin,3 another agent. An important feature of this
leukin-2 (IL-2) receptor expressed on the J. S. Skyler,8 Type 1 Diabetes TrialNet study is the demonstration that B-lympho-
surface of activated lymphocytes, and has Anti-CD20 Study Group cytes contribute to the pathogenesis of T1D.
1
been effective in other autoimmune diseases Indiana University School of Medicine, This may have important implications for the
as well as in islet transplant protocols. The Indianapolis, IN, USA, 2Benaroya Research design of combination therapy regimens for
combination of MMF and DZB had a bene- Institute, Seattle, WA, USA, 3George Washing- evaluation in T1D.
ficial synergistic effect in diabetic animal ton University Biostatistics Center, Rockville,
models. MD, USA, 4University of Pittsburgh, Pitts- Six months of diazoxide
Methods: The study included 126 subjects, burgh, PA, USA, 5University of California, San
Francisco, CA, USA, 6Columbia University, treatment at bedtime in newly
ages 8–45, randomised to MMF alone, MMF
plus DZB, or placebo. Two DZB (or placebo) New York, NY, USA, 7University of Colorado diagnosed subjects with type 1
infusions were administered – one initially Barbara Davis Center for Childhood Diabetes, diabetes does not influence
and one 2 weeks later. MMF (or placebo) was Aurora, CO, USA, 8University of Miami Dia-
betes Institute, Miami, FL, USA, 9University of parameters of b-cell function
given continuously, with a planned study
end-point at 2 years. Minnesota, Minneapolis, MN, USA, 10Univer- and autoimmunity but improves
Results: The Data Safety and Monitoring sity of Texas Southwestern Medical School, Dal- glycaemic control
Board halted the study early due to the pro- las, TX, USA, 11University of Florida,
jected futility of achieving a beneficial result. Gainesville, FL, USA, 12Hospital for Sick Chil- M. A. Radtke,1,2 I. Nermoen,3 M. Kollind,4
There was a similar decline in b-cell func- dren, University of Toronto, Toronto, ON, S. Skeie,5 J. I. Sørheim,6 J. Svartberg,7,8
tion in all three groups – MMF alone, MMF Canada, and 13Stanford University, Stanford, I. Hals,1 T. Moen,9 G. H. Dørflinger,1
plus DZB, and placebo. In addition, A1c and CA, USA V. Grill1,2
1
insulin dosage were similar in all three N Engl J Med 2009; 361: 2143–52 Department of Cancer Research and Molec-
groups. ular Medicine, Norwegian University of Science
Conclusions: MMF, either alone or in Background: There is growing evidence and Technology, Trondheim, Norway, 2Depart-
combination with DZB, failed to prevent that B-lymphocytes play a role in many ment of Endocrinology, St Olavs Hospital ⁄

ª 2011 Blackwell Publishing Ltd Int J Clin Pract, February 2011, 65 (Suppl. 170), 61–70
64 Immunomodulation

University Hospital of Trondheim, Trondheim, have been a consequence of greater insulin interrupt the immune processes that result in
Norway, 3Department of Endocrinology, Akers- sensitivity and less weight gain in the diazox- T1D. Such therapies are generally quite safe,
hus University Hospital, Lørenskog, Norway, ide group. The authors propose that low-dose are specific for T1D, and are not expected to
4
Endocrinology Unit, Department of Internal diazoxide could serve as a component in a alter generalised immune responses. The insu-
Medicine, Levanger Hospital, Levanger, Nor- combination therapy regimen. Indeed, that lin B (9-23) APL (Ala16,19) (NBI-6024) was
way, 5Section of Endocrinology, Division of may be worth exploring. shown to alter the course of diabetes in the
Medicine, Stavanger University Hospital, NOD mouse and prevented activation of both
Stavanger, Norway, 6Section of Endocrinology, murine and human T-lymphocytes in the lab-
Department of Medicine, Haukeland University No effect of the altered peptide oratory. Preliminary studies demonstrated
Hospital, Bergen, Norway, 7Section of Endocri- ligand NBI-6024 on b-cell that there were no safety issues. Thus, the
nology, Division of Internal Medicine, Univer- current dose-ranging study was awaited with
sity Hospital of North Norway, Tromsø, residual function and insulin considerable enthusiasm. The study was well
Norway, 8Institute of Clinical Medicine, needs in new-onset type 1 designed and carefully conducted. Unfortu-
University of Tromsø, Tromsø, Norway, and diabetes nately, the APL had no impact on b-cell func-
9
Department of Laboratory Medicine, tion. A critical question is whether an
Children’s and Women’s Health, Faculty of M. Walter,1 A. Philotheou,2 F. Bonnici,2 adequate dose was given. It is impossible to
Medicine, Norwegian University of Science and A. G. Ziegler,1 R. Jimenez,3 NBI-6024 Study measure blood levels of the APL or a marker
Technology, Trondheim, Norway Group that would indicate that a given dose was
1
Diabetes Care 2010; 33: 589–94 Diabetes Research Institute, Forschergruppe altering some biological response. This is a
Diabetes e.V., Munich, Germany, 2Diabetes vexing question that has hampered other
Background: Diazoxide provides b-cell rest Clinical Trials Unit, Faculty of Health Sciences, studies with antigen-specific interventions.
by reversibly suppressing glucose-induced University of Cape Town, Cape Town, South Extrapolation of effective doses from mice to
insulin secretion. Previous studies have shown Africa, and 3Clinical Development, Neurocrine human beings is always a game of roulette. It
that diazoxide may preserve b-cell function in Biosciences, San Diego, CA, USA is unlikely that this particular APL will be
recent-onset T1D, but with frequent adverse Diabetes Care 2009; 32: 2036–40 further pursued. That is unfortunate.
effects consisting of lanugo hair growth,
oedema and hypotension. The current study Background: Insulin B (9–23) peptide is
Autoantigen-specific regulatory
was designed to test whether a lower dosage thought to be an important antigen of T-lym-
of diazoxide would eliminate side effects and phocytes in autoimmune diabetes in animals T cells induced in patients with
still exert beneficial effects. and in human beings. It is possible to target type 1 diabetes mellitus by
Methods: The study randomised 41 sub- specific autoreactive T-lymphocyte activation
insulin B-chain immunotherapy
jects (22 to diazoxide, 19 to placebo), ages using a soluble altered peptide ligand (APL)
18–40, with recent-onset T1D. Subjects to block or change that activation. NBI-6024 T. Orban,1 K. Farkas,1 H. Jalahej,1 J. Kis,1,2
received 6 months of treatment with placebo is an APL that contains two amino acid A. Treszl,1,3 B. Falk,4 H. Reijonen,4
or 100 mg diazoxide at bedtime, and were substitutions in the (9–23) sequence of the J. Wolfsdorf,5 A. Ricker,1 J. B. Matthews,6
followed for a subsequent 6 months. Out- B-chain of insulin: alanine is substituted for N. Tchao,6 P. Sayre,6 P. Bianchine7
come measures were C-peptide (fasting and tyrosine at position 16, which is a key contact 1
Joslin Diabetes Center, Boston, MA, USA,
glucagon stimulated), A1c and insulin dose. site at the T-lymphocyte receptor; and alanine 2
Polyclinic of the Hospitaller Brothers, Buda-
Results: A1c levels at both 6 months and also is substituted for cysteine at position 19. pest, Hungary, 3Zentrum für Experimentelle
1 year were lower in the diazoxide group, but The resulting APL (Ala16,19) (also known as Medizin Institut für Medizinische Biometrie
there was no difference in insulin dose, NBI-6024) does not activate insulin B (9–23) und Epidemiologie, Hamburg, Germany,
C-peptide levels (either actual levels or reactive murine or human T-lymphocytes. 4
Benaroya Research Institute at Virginia
C-peptide ⁄ glucose ratios), or in proportion of Methods: The study randomised 188 sub- Mason, Seattle, WA, USA, 5Children’s Hospital
Tregs (regulatory T-lymphocytes). There was jects, ages 10–35, to three different doses of Boston, MA, USA, 6Immune Tolerance Net-
more weight gain in the placebo group. the APL (50 subjects to 0.1 mg, 48 subjects to work, University of California, San Francisco,
Insulin sensitivity, as assessed by HOMA-S% 0.5 mg, 43 subjects to 1.0 mg) or to placebo CA, USA, and 7National Institute of Allergy
(homeostatic model assessment for insulin (47 subjects). Intervention consisted of subcu- and Infectious Diseases, Bethesda, MD, USA
sensitivity), increased in the diazoxide group taneous injections at randomisation, 2 weeks, J Autoimmun 2010; 34: 408–15
but remained stable in the placebo group. 4 weeks and monthly until 24 months. The
Conclusions: Low dose diazoxide averted primary end-point was b-cell function – as Background: Insulin B-chain contains the
adverse effects but failed to improve outcome measured by C-peptide – at 2 years. insulin B (9–23) peptide, which is a major
in recent-onset T1D. Results: At 2 years, the mean peak C-pep- epitope recognised by the immune system
• Comment: Diazoxide, at higher doses, has tide concentration showed no significant dif- and thought to be a diabetes-specific antigen.
previously been shown to have beneficial ference between any of the treated groups and The insulin B-chain fragment is metabolically
effects in preserving b-cell function in recent- the placebo group. C-peptide declined linearly inactive. Incomplete Freund’s adjuvant (IFA)
onset T1D. However, its use has been limited in all groups. has been used in a number of vaccines as a
due to intolerability from side effects. In the Conclusions: The insulin B (9–23) APL delivery system that promotes regulatory
current randomised controlled trial, a lower (Ala16,19) (NBI-6024) failed to show benefit in immune responses. The current report
dose was better tolerated but failed to demon- any of three doses tested in a large dose- describes a pilot study testing insulin B-chain
strate preservation of b-cell function. Interest- ranging study. administered with IFA in T1D.
ingly, there were differences in A1c, which • Comment: Antigen-specific therapy is Methods: The study randomised 12 sub-
was lower in the diazoxide group. This may thought to be a highly desirable strategy to jects (six to 2 mg insulin B-chain in IFA, six

ª 2011 Blackwell Publishing Ltd Int J Clin Pract, February 2011, 65 (Suppl. 170), 61–70
Immunomodulation 65

to placebo, IFA alone), ages 18–35, with No effect of the 1a,25- Medical Statistics Unit, London School of
recent-onset T1D. Subjects received a single Hygiene and Tropical Medicine, London, UK,
intramuscular injection of test substance, and
dihydroxyvitamin D3 on b-cell 5
Department of Pediatrics, University of
were followed for 2 years. Outcome measures residual function and insulin Turku, Turku, Finland, 6Department of
were b-cell function – as measured by C-pep- requirement in adults with Pediatrics, University of Oulu, Oulu, Finland,
7
tide – and insulin-specific humoral and Immunogenetics Laboratory, University of
T-lymphocyte responses.
new-onset type 1 diabetes Turku, Turku, Finland, 8Department of
Results: There was no statistical difference M. Walter,1 T. Kaupper,1 K. Adler,1 J. Foersch,1 Clinical Microbiology, University of Eastern
in b-cell function, measured every 6 months, E. Bonifacio,2 A. G. Ziegler1 Finland, Kuopio, Finland, 9Department of
between arms. All patients in the experimen- 1 Pediatrics, Tampere University Hospital,
Diabetes Research Institute, Forschergruppe
tal group who received insulin B-chain, but Diabetes e.V., Munich, Germany, and Tampere, Finland, 10Hospital for Children and
none who received placebo, developed robust 2 Adolescents and Folkhälsan Research Center,
Deutsche Forschungsgemeinschaft Center for
insulin-specific humoral and T-lymphocyte Regenerative Therapies, Dresden, Germany University of Helsinki, Helsinki, Finland, and
11
responses, including insulin B-chain-specific Diabetes Care 2010; 33: 1443–8 Research Unit, Tampere University Hospital,
CD4+ T-lymphocytes that were cloned and Tampere, Finland
showed characteristics of regulatory T-lym- Background: Mechanistic studies show that Diabetologia 2010; 53: 1599–607
phocytes. 1a,25-dihydroxyvitamin D3 [1,25(OH)2D3]
Conclusions: Insulin B-chain, given modulates dendritic cell maturation in vitro Background: Maternal intake of vitamin D
together with IFA, may beneficially impact and in vivo and facilitates a shift from a Th1 from food or use of vitamin-D-containing
immune response in T1D. to a Th2 immune response. Studies in the supplements during pregnancy was weakly
• Comment: This is another test of an anti- NOD mouse show that 1,25(OH)2D3 reduces associated with decreased risk of early b-cell
gen-specific therapy in T1D. It was only a the incidence of insulitis and diabetes. Thus, autoimmunity in two cohort studies and with
very small pilot study involving 12 subjects, the current study was conducted to determine clinical T1D in one case–control study.
six who received a single injection of insulin whether 1,25(OH)2D3 is safe and improves b- Methods: Mothers of 3723 infants born
B-chain in IFA, and six who received IFA cell function in patients with recent-onset between 1997 and 2002 completed a 181-item
alone. Although claimed to be safe, it is T1D. food frequency questionnaire, including ques-
impossible to assess safety in such a small Methods: Two studies were conducted – a tions on dietary supplements. Offspring were
study. Also impossible to assess in a small safety study in 25 subjects, all treated with observed at 3–12 month intervals for appear-
study is b-cell function, which here was care- 1,25(OH)2D3 and followed for 18 months, ance of T1D-associated autoantibodies and
fully measured with meal tolerance tests. and an efficacy study in which 40 subjects, for the development of T1D.
Although there was no statistical difference ages 18–39, with recent-onset T1D, were Results: Maternal mean daily intake of
between groups, the C-peptide levels were randomised either to 1,25(OH)2D3 (n = 22) vitamin D was 5.1 lg from food and 1.3 lg
persistently higher in the placebo group. Had or to placebo (n = 18). The primary end- from supplements. Maternal intake of vitamin
the results been reversed, it would not be sur- point was b-cell function – as measured by D, either from food or from supplements,
prising for the authors to claim a beneficial C-peptide – at 18 months. Careful safety was not associated with the risk of b-cell au-
‘trend’. This illustrates the difficulty in inter- assessments were performed. toimmunity or with the risk of T1D in off-
pretation of small pilot studies. Intriguingly, Results: There was a similar decline in b- spring.
the cloned T-lymphocytes from the experi- cell function in both groups – 1,25(OH)2D3 Conclusions: Maternal intake of vitamin D
mental group had characteristics of regulatory and placebo. In addition, A1c and insulin did not appear to influence the T1D process
T-lymphocytes. But, what if there was also dosage were similar in both groups. The in offspring.
activation of effector T-lymphocytes that was treatment was safe. • Comment: For some time, the potential
not demonstrated. Could that have resulted Conclusion: 1,25(OH)2D3 was shown to be role of vitamin D as a preventative interven-
in a subtle greater loss of b-cell function? safe, but did not have a beneficial effect in tion for T1D has been raised. There are
Despite these questions, the results are suffi- adults with recent-onset T1D. clearly effects of vitamin D in vitro and some
ciently provocative to support further studies beneficial effects in animal models, particu-
with insulin B-chain. Questions that can be larly in vitamin-D-deficient animals. In
raised, however, are whether 2 mg is the right Maternal intake of vitamin D human beings, cohort studies and meta-analy-
dose and whether a single intramuscular vac- during pregnancy and risk of ses of studies done in infants have suggested
cination is the right number of vaccinations. potential benefit. Thus, the use of vitamin D
Only full-scale dose-ranging studies can
advanced b-cell autoimmunity
remains an attractive hypothesis for preven-
answer these questions. These preliminary and type 1 diabetes in offspring tion of T1D, the best case being for its use in
data suggest that such studies are warranted. infants. In the two studies described above,
L. Marjamäki,1 S. Niinistö,2,3 M. G. Kenward,4
L. Uusitalo,1,2 U. Uusitalo,2 M. L. Ovaskainen,2 there was no support for this hypothesis. The
C. Kronberg-Kippilä,2 O. Simell,5 R. Veijola,6 intervention study with 1,25(OH)2D3 was
J. Ilonen,7,8 M. Knip,9,10 S. M. Virtanen1,2,9,11 conducted in adults after the development of
1
Tampere School of Public Health, Univer- T1D. Although a small study, it failed to
sity of Tampere, Tampere, Finland, 2Depart- show a beneficial effect. Intervention with
vitamin D at that stage might not be expected
ment of Lifestyle and Inclusion, National
Institute for Health and Welfare, Helsinki, to have beneficial effects. The Finnish study
evaluated maternal intake of vitamin D and
Finland, 3Department of Public Health, Uni-
versity of Helsinki, Helsinki, Finland, 4Depart- whether it correlated with b-cell autoimmuni-
ty or with the risk of T1D in offspring. There
ment of Epidemiology and Population Health,

ª 2011 Blackwell Publishing Ltd Int J Clin Pract, February 2011, 65 (Suppl. 170), 61–70
66 Immunomodulation

are two important points to note, however. Autologous umbilical cord blood or more probably to the effects of the pro-
First, this was not an intervention study, found immunosuppression given at the out-
which might better have permitted assessment
transfusion in very young set with AHSCT serving to rescue the patient
of the impact of vitamin D. Second, although children with type 1 diabetes from death from destruction of their
the food questionnaire has been validated, it immune system. Thus, in human beings there
M. J. Haller,1 C. H. Wasserfall,2
is difficult to assess how well it reflected vita- is no clear evidence yet of beneficial effects
K. M. McGrail,2 M. Cintron,1 T. M. Brusko,3
min D intake, and whether the range of vita- of any cellular treatment per se in T1D (other
J. R. Wingard,4 S. S. Kelly,5 J. J. Shuster,6
min D intake was sufficient to allow than pancreatic or islet transplantation). The
M. A. Atkinson,2 D. A. Schatz1
assessment of its impact. 1 two studies described above also failed to
Department of Pediatrics, University of
show beneficial effects. These negative out-
Florida, Gainesville, FL, USA, 2Department of
comes, however, should not be cited as a rea-
Regeneration of insulin Pathology, University of Florida, Gainesville,
son to halt research of cellular therapies. In
production by autologous bone FL, USA, 3Diabetes Center, University of Cali-
animal models and laboratory experiments,
fornia at San Francisco, San Francisco, CA,
marrow blood USA, 4Department of Medicine, University of
there is clearly much promise for cellular
based therapies. Eventually, success will be
autotransplantation in patients Florida, Gainesville, FL, USA, 5Department of
achieved.
with type 1 diabetes Pediatrics, University of Texas, Houston, TX,
USA, and 6Department of Epidemiology and
E. Esmatjes,1,6,7 X. Montaña,2 M. I. Real,2 Health Policy Research and the General Clini- Developing combination
J. Blanco,1 I. Conget,1,6,7 R. Casamitjana,3,6,7 cal Research Center, University of Florida,
M. Rovira,4,6 R. Gomis,1,6,7 P. Marin5,6
immunotherapies for type 1
Gainesville, FL, USA
1
Diabetes Unit, Hospital Clinic Universitari, Diabetes Care 2009; 32: 2041–6 diabetes: recommendations
Barcelona, Spain, 2Interventional Angioradiolo- from the ITN-JDRF Type 1
gy Unit, Hospital Clinic Universitari, Barce- Background: Umbilical cord blood con-
lona, Spain, 3Biochemistry and Molecular
Diabetes Combination Therapy
tains a population of immature unprimed
Genetics Department, Hospital Clinic Universi- functional regulatory T-lymphocytes. These Assessment Group
tari, Barcelona, Spain, 4Bone Marrow Trans- cells could, in theory, limit inflammatory J. B. Matthews,1 T. P. Staeva,2 P. L. Bernstein,1
plant Unit, Hospital Clinic Universitari, cytokine responses and anergize effector M. Peakman,4,5 M. von Herrath,3 and
Barcelona, Spain, 5Hemotherapy Unit, Hospital T-lymphocytes, which are thought to mediate ITN-JDRF Type 1 Diabetes Combination
Clinic Universitari, Barcelona, Spain, 6Institut cellular autoimmune processes. Therapy Assessment Group
d’Investigacions Biomèdiques August Pii Sunyer Methods: Children aged > 1 year who 1
Immune Tolerance Network, San Francisco,
(IDIBAPS), Barcelona, Spain, and 7CIBER de developed T1D and had banked umbilical CA, USA, 2Juvenile Diabetes Research Founda-
Diabetes y Enfermedades Metabólicas Asociadas cord blood at an approved centre were tion International, New York, NY, USA, 3La
(CIBERdem), Barcelona, Spain recruited into this study. Fifteen subjects Jolla Institute for Allergy and Immunology, La
Diabetologia 2010; 53: 786–9 enrolled in an open-label phase 1 study using Jolla, CA, USA, 4Department of Immunology,
autologous umbilical cord blood infusion. King’s College London, UK, and 5NIHR Bio-
Background: Some experimental reports They were followed for 1 year. medical Research Center at Guy’s and St Tho-
suggest that the bone marrow harbours cells Results: There was no evidence at 1 year of mas’ NHS Foundation Trust and King’s
capable of differentiation into b-cells, or as a maintenance of preservation of b-cell function College London, London, UK
facilitator of b-cell regeneration, or as an – as measured by C-peptide – while insulin Clin Exp Immunol 2010; 160: 176–84
immune modulator, and thus use of bone doses increased over time. No changes were
marrow cells has been proposed as treatment observed in autoantibody titres, regulatory T-
• Comment: This paper describes the results
for T1D. lymphocyte numbers, or other immune
of a workshop conducted by the Immune
Methods: A pilot study was conducted in parameters. There were no significant adverse
Tolerance Network (ITN) and the Juvenile
three subjects with established T1D and events.
Diabetes Research Foundation (JDRF) to
absent b-cell function. Autologous bone mar- Conclusions: Autologous umbilical cord
review strategies for developing combination
row was harvested and subsequently injected blood infusion was safe, but had no beneficial
therapies for T1D. The advantages of a com-
via selective arteriography as an intra- effect in children with T1D.
bination strategy include the ability to mini-
pancreatic infusion. • Comment: Many investigators believe that
mise toxicities and realise synergies to
Results: Data were available for two cellular therapies for T1D hold substantial
enhance and prolong efficacy. The paper
of the three subjects. There was no evidence promise. A study from Brazil (1) discussed in
notes that a clear framework must be devel-
of b-cell function during 6 months of last year’s Yearbook evaluated the effects of
oped that specifies the type and quality of
follow-up. non-myeloablative autologous haematopoietic
preclinical data, including which animal mod-
Conclusions: Intrapancreatic autologous stem cell transplantation (AHSCT) in recent-
els are acceptable, as well as toxicology and
bone marrow infusion had no impact in two onset T1D. In that study, 20 of 23 subjects
pharmacodynamic data expectations that will
subjects with long-standing T1D. became insulin free, some for protracted
be required for a combination to meet
periods of time. Although many have attrib-
acceptable safety standards to justify human
uted the results to the infused cells, it is not
trials. It points out that there is a major need
possible to distinguish whether the putative
for surrogate end-points based upon benefi-
effects of AHSCT were due to immune
cial immunological responses that manifest
reconstitution or otherwise altering the
soon after treatment, which would facilitate
immune-mediated b-cell destruction that
rapid assessment and prioritisation of any
eventuates in T1D, to regeneration of b-cells,

ª 2011 Blackwell Publishing Ltd Int J Clin Pract, February 2011, 65 (Suppl. 170), 61–70
Immunomodulation 67

6
individual T1D therapeutic and would be par- Results: Progressors to T1D and non-pro- Division of Endocrinology ⁄ Metabolism, Uni-
ticularly important for selection of potential gressors had similar baseline insulin sensitiv- versity of Washington, Seattle, WA, USA,
combinations. The paper notes that biomar- ity, fasting insulin secretion and total post- and 7Division of Endocrinology, University of
kers could speed clinical assessments by pro- glucose insulin output. In contrast, b-cell glu- Florida, Gainesville, FL, USA
viding surrogate end-points, permit cose sensitivity was impaired at baseline and Diabetes Care 2009; 32: 2269–74
stratification of analysis of trial data, and predicted development of diabetes. Moreover,
facilitate personalised medicine by informing glucose sensitivity began to decline signifi- Background: In another report from the
treatment decisions. The authors gave priority cantly before any changes in plasma glucose, DPT-1 studies, the prediction of T1D by spe-
rankings of combination immune-based ther- while insulin secretion and insulin sensitivity cific types of pancreatic islet autoantibodies,
apies for T1D, favouring approved agents, remained stable. either alone or in combination, was explored.
favouring combination of immune modula- Conclusions: A defect in b-cell glucose Methods: The study included two cohorts
tors with antigen-specific therapies, and limit- sensitivity is detectable in at-risk subjects from DPT-1, both derived from initial screen-
ing initial proposals to two agents in years before diagnosis, and anticipates plasma ing for islet cell autoantibodies (ICAs). Also
combination. The paper is cognizant of regu- glucose increments. measured were antibodies to GAD65, ICA512
latory hurdles and the need for negotiations • Comment: The failure of the b-cell to and insulin. Participants were followed for
with commercial sponsors. It is a solid paper adequately respond to glucose – b-cell the occurrence of T1D. One cohort, called
worth reading by anyone conducting investi- ‘blindness’ to glucose – is a characteristic ‘Trials’, included 528 DPT-1 participants
gations in the field. pathophysiological abnormality in both T1D (83.3% ICA+) who were randomised in the
and type 2 diabetes. It results in a lack of DPT-1 studies. The other cohort, called
adequate early insulin secretory response ‘Questionnaire’, included 28,507 individuals
MECHANISMS, MARKERS, that eventuates in significant postprandial (2.4% ICA+) who did not enter the DPT-1
TRIGGERS, PATHOLOGY hyperglycaemia. Here it is demonstrated that trials but responded to questionnaires as to
this defect is present very early in the dis- T1D status.
The second group of papers includes reports
ease process, before other metabolic abnor- Results: In both cohorts autoantibody
of studies in human T1D that focus on mech-
malities. Teleologically, it may be a way the number was highly predictive of T1D. In the
anisms, markers, triggers and pathology.
injured b-cell manifests itself. Presumably, Questionnaire cohort, as single autoantibod-
in T1D, the b-cell has been injured via ies, ICA (3.9%), GAD65 (4.4%) and ICA512
Progression to diabetes in immunological attack. Indeed, if humoral (4.6%) were similarly predictive of T1D,
anti-islet antibodies are a marker of the whereas no subjects with only insulin autoan-
relatives of type 1 diabetic
immune attack, all of the subjects included tibodies developed T1D.
patients: mechanisms and mode in DPT-1 already had that under way, as Conclusions: The number of autoantibod-
of onset an entry criterion was presence of antibod- ies is predictive of T1D. However, there are
ies. It would be interesting to do similar differences in prediction based on antibody
E. Ferrannini,1 A. Mari,2 V. Nofrate,2 modelling in studies involving genetically type and titre.
J. M. Sosenko,3 J. S. Skyler,3 DPT-1 Study high risk individuals who do not yet have • Comment: The finding that autoantibody
Group anti-islet antibodies, as it is possible that a number predicts T1D is consistent with other
1
Department of Medicine, University of Pisa defect in b-cell glucose sensitivity is geneti- studies. However, this represents the largest
School of Medicine, Pisa, Italy, 2C.N.R. Insti- cally determined and may indicate that a prospective study of relatives yet to be
tute of Biomedical Engineering, Padua, Italy, particular subject is more vulnerable to reported. It confirms that an individual with
and 3Division of Endocrinology, University of immune-mediated damage. only a single antibody being positive is far less
Miami, Miami, FL, USA likely to develop T1D than those with two or
Diabetes 2010; 59: 679–85 more antibodies. It also finds that the particu-
Pancreatic islet autoantibodies
lar type and titre of an autoantibody can
Background: The Diabetes Prevention Trial as predictors of type 1 diabetes influence prediction. Over the years, our tools
– Type 1 (DPT-1) studied relatives of T1D in the Diabetes Prevention for prediction of T1D have continued to
patients at enhanced risk of developing T1D. improve. This has been demonstrated in the
This study explored the mode of onset of hy- Trial – Type 1
DPT-1 studies, in the ENDIT (European Nic-
perglycaemia and how insulin sensitivity and T. Orban,1 J. M. Sosenko,2 D. Cuthbertson,3 otinamide Diabetes Intervention Trial) study
b-cell function contribute to the progression J. P. Krischer,4 J. S. Skyler,2 R. Jackson,1 and many others. Yet, the focus of many
of the disease. L. Yu,5 J. P. Palmer,6 D. Schatz,7 studies has been on relatives of individuals
Methods: The study analysed results from G. Eisenbarth,5 Diabetes Prevention Trial – with T1D. It is probably time to advance
328 non-diabetic relatives from the control Type 1 Study Group screening and prediction efforts more widely
arms of the DPT-1 studies. Subjects had 1
Joslin Diabetes Center, Boston, MA, USA, into the general population. This might best
sequential oral glucose tolerance tests per- 2
Division of Endocrinology, University of be accomplished with screening at birth for
formed at baseline, every 6 months, and an Miami, Miami, FL, USA, 3Pediatrics Epidemi- high risk HLA genotypes, as has been done in
average of 2.7 years later, when 115 subjects ology Center, University of South Florida, studies such as DIPP (Diabetes Prediction
became diabetic. b-cell glucose sensitivity Tampa, FL, USA, 4Division of Informatics and and Prevention), DAISY (Diabetes Autoim-
(slope of the insulin secretion ⁄ plasma glucose Biostatistics, University of South Florida, munity Study in the Young) and TEDDY
dose–response function) and insulin sensitiv- Tampa, FL, USA, 5Barbara Davis Center for (The Environmental Determinants of Diabetes
ity were obtained by mathematical modelling Childhood Diabetes, Denver, CO, USA, in the Young).
of the oral glucose tolerance test glucose ⁄ C-
peptide responses.

ª 2011 Blackwell Publishing Ltd Int J Clin Pract, February 2011, 65 (Suppl. 170), 61–70
68 Immunomodulation

Preservation of b-cell function • Comment: The SEARCH study data, as well likely to breastfeed their children or breast-
as the control groups in the intervention feed for a shorter period of time than non-
in autoantibody-positive youth studies discussed earlier, clearly demonstrate diabetic mothers. The aim of this study was
with diabetes that b-cell function is not rapidly lost after to prospectively examine the breastfeeding
diagnosis of diabetes, but rather that over patterns among mothers with and without
C. J. Greenbaum,1 A. M. Anderson,2
80% of youth have significant residual b-cell T1D.
L. M. Dolan,3 E. J. Mayer-Davis,4 D. Dabelea,5
function within the first year of diagnosis, Methods: Families from an infant feeding
G. Imperatore,6 S. Marcovina,7 C. Pihoker,8
and 10% continue to have significant residual study (TRIGR) included 2160 babies; 1096
SEARCH Study Group
1 b-cell function after 5 years. This may have were born to women with T1D and 1064 to
Diabetes Research Program, Benaroya
important implications as successful interven- unaffected women. Information on infant
Research Institute, Seattle, WA, USA, 2Wake
tion strategies evolve, as those with significant feeding was acquired by frequent prospective
Forest University School of Medicine, Winston-
residual b-cell function may potentially bene- dietary interviews.
Salem, NC, USA, 3Cincinnati Children’s Hospi-
fit from intervention, which in most trials is Results: Most (> 90%) of the infants were
tal and Medical Center, Cincinnati, OH, USA,
4 currently being studied only in recent-onset initially breastfed, regardless of the mother’s
Department of Nutrition, University of North
T1D. T1D status. However, breastfeeding rates
Carolina at Chapel Hill, Chapel Hill, NC, and
declined more steeply among mothers with
the Department of Epidemiology and Biostatis-
T1D than without T1D, being 50% and 72%
tics, University of South Carolina, Columbia, Breastfeeding patterns of at 6 months, respectively. After adjusting for
SC, USA, 5Department of Epidemiology, Colo-
mothers with type 1 diabetes: age, educational status, timing of delivery and
rado School of Public Health, University of Col-
results from an infant feeding caesarean section rate, all factors associated
orado, Denver, CO, USA, 6Division of Diabetes
with the termination of breastfeeding, there
Translation, National Center for Chronic Dis- trial was no difference in the duration of breast-
ease Prevention and the Health Promotion
S. Sorkio,1 D. Cuthbertson,2 S. Bärlund,1 feeding among mothers with and without
Centers for Disease Control and Prevention,
A. Reunanen,3 A. M. Nucci,4 C. L. Berseth,5 T1D.
Atlanta, GA, USA, 7Department of Medicine,
K. Koski,6 A. Ormisson,7 E. Savilahti,8 Conclusions: Maternal diabetes status was
University of Washington, Seattle, WA, USA,
U. Uusitalo,2 J. Ludvigsson,9 D. J. Becker,10 not itself associated with shorter breastfeed-
and 8Department of Pediatrics, University of
J Dupré,11 J. P. Krischer,2 M. Knip,8,12,13 ing. Shorter duration of breastfeeding in
Washington, Seattle, WA, USA
H. K. Akerblom,6 S. M. Virtanen,1,14,15 TRIGR mothers with T1D could be explained by
Diabetes Care 2009; 32: 1839–44
Study Group their more frequent caesarean sections, earlier
1
Nutrition Unit, National Institute for delivery and lower age and education.
Background: SEARCH is a population- • Comment: Although mothers with T1D
based study conducted at six centres in the Health and Welfare, Helsinki, Finland,
2
Pediatrics Epidemiology Center, University of breastfed for a shorter duration, this did not
USA, including existing (prevalent) and newly seem to be related to T1D itself, but rather to
diagnosed (incident) cases of diabetes in South Florida, Tampa, FL, USA, 3National
Institute for Health and Welfare, Helsinki, other confounding factors, i.e. differences in
youth. This report describes the extent of b- the mode of delivery, length of gestation,
cell function in youth with diabetes who have Finland, 4Division of Nutrition, School of
Health Professions, College of Health and parental age and education. Breastfeeding has
GAD65 and ⁄ or IA2 autoantibodies. substantial health advantages and thus is
Methods: Fasting C-peptide levels were Human Sciences, Georgia State University,
Atlanta, GA, USA, 5Bristol-Myers Squibb, desirable for all infants, and should be
obtained from 2789 GAD65 and ⁄ or IA2 auto- encouraged. It also may impact the frequency
antibody-positive youth aged 1–23 years. Pre- Evansville, IN, USA, 6Institute of Clinical
Medicine, University of Helsinki, Helsinki, of development of T1D. Yet, the TRIGR study
served b-cell function was defined on the (2), from which this study is derived, is eval-
basis of cut points derived from the Diabetes Finland, 7Department of Paediatrics, University
of Tartu, Tartu, Estonia, 8Hospital for Children uating the content of infant formula – cow’s
Control and Complications Trial (DCCT) milk based versus casein hydrolysate – in
(fasting C-peptide ‡ 0.23 ng ⁄ ml) and from and Adolescents, University of Helsinki,
Helsinki, Finland, 9 Division of Pediatrics, order to ascertain whether early introduction
the adolescent population of the National of cow’s milk may serve as an environmental
Health and Nutrition Examination Survey Department of Health and Environment,
Faculty of Health Sciences, University of trigger for T1D. It will be several years before
(NHANES) 5th percentile for fasting C-pep- the results of this important study become
tide (‡ 1.0 ng ⁄ ml). The clinical characteristics Linköping, Linköping, Sweden, 10Children’s
Hospital of Pittsburgh, Pittsburgh, PA, USA, available. In the meantime, breastfeeding
between those with and without preserved b- 11 defers the introduction of any formula, and
cell function were compared. Robarts Research Institute, London, ON,
Canada, 12Folkhlsan Research Center, prolonged breastfeeding may be beneficial in
Results: Within the first year of diagnosis, terms of forestalling T1D. It would be unfor-
82.9% of youth had a fasting C-peptide University of Helsinki, Helsinki, Finland,
13
Department of Pediatrics, Tampere University tunate if the presence of maternal T1D
‡ 0.23 ng ⁄ ml and 31.2% had values directly led to shorter duration of breastfeed-
‡ 1.0 ng ⁄ ml. Among those with 5 or more Hospital, Tampere, Finland, 14Tampere School
of Public Health, University of Tampere, ing. This study also highlights a separate
years of diabetes, 10.7% had preserved b-cell issue. Namely, one has to wonder whether
function based on the DCCT cutoff and 1.0% Tampere, Finland, and 15Research Unit,
Tampere University Hospital, Tampere, Finland greater efforts should be made to have
were above the NHANES 5th percentile. women with T1D progress to spontaneous
Conclusions: Early on, the vast majority of Diabetes Metab Res Rev 2010; 26: 206–11
labour and vaginal delivery in contrast to the
antibody-positive youth with diabetes have not uncommon practice of early delivery by
significant residual b-cell function, but by Background: It had previously been
reported that mothers with T1D are less caesarean section.
5 years of diabetes, only 10% do.

ª 2011 Blackwell Publishing Ltd Int J Clin Pract, February 2011, 65 (Suppl. 170), 61–70
Immunomodulation 69

Prevalence of enteroviral capsid are important in the aetiology or pathogenesis during immunosuppressive therapy showed
of T1D may facilitate the development of that autoimmunity was not resolved by the
protein vp1 immunostaining in intervention strategies to reduce or eliminate agents used.
pancreatic islets in human type the impact of such factors, and thus may be Conclusions: Recurrent autoimmunity may
1 diabetes important in the eventual prevention of T1D. be responsible for hyperglycaemia recurrence
in pancreatic transplant recipients, despite
S. J. Richardson,1 A. Willcox,1 A. J. Bone,2 immunosuppressive therapy.
A. K. Foulis,3 N. G. Morgan1 Recurrence of type 1 diabetes • Comment: Loss of function after time is a
1
Institute of Biomedical and Clinical Sci- after simultaneous pancreas– common feature in recipients of pancreas or
ences, Peninsula Medical School, Plymouth, islet transplants. There are many possible rea-
kidney transplantation, despite
UK, 2School of Pharmacy and Biomolecular sons for this, one of which is the recurrence
Sciences, University of Brighton, Brighton, UK, immunosuppression, is of autoimmunity. Yet, it might be expected
and 3Department of Pathology, Royal Infir- associated with autoantibodies that the immunosuppressive agents used to
mary, Glasgow, UK prevent allograft rejection would also prevent
and pathogenic autoreactive
Diabetologia 2009; 52: 1143–51 recurrent autoimmunity. In the patients
CD4 T-cells described here, that is clearly not the case, as
Background: Much evidence suggests that F. Vendrame,1 A. Pileggi,1,2 E. Laughlin,3 there was no evidence of rejection either in
enterovirus infection may be an important G. Allende,1 A. Martin-Pagola,1 R. D. Molano,1 the pancreas biopsy or in the function of the
environmental trigger of T1D. This study S. Diamantopoulos,1 N. Standifer,3,4 transplanted kidney. Yet, biopsies revealed b-
examined pancreatic islets in autopsy speci- K. Geubtner,3 B. A. Falk,3 H. Ichii,1,2 cell loss and insulitis, and both autoantibodies
mens for evidence of enteroviral infection. H. Takahashi,2 I. Snowhite,1 Z. Chen,5 and autoreactive T-lymphocytes were demon-
Methods: Pancreatic autopsy specimens A. Mendez,1,6 L. Chen,2 J. Sageshima,2 strable. This causes one to conclude that the
were examined, including 72 from recent- P. Ruiz,2 G. Ciancio,2 C. Ricordi,1,2,5,6 mechanisms responsible for allograft rejection
onset T1D (mean age 12.65 ± 1.1 years, range H. Reijonen,3 G. T. Nepom,3 G. W. Burke,1,2 and for autoimmunity are different, and may
1–42 years, and a mean time since diagnosis A. Pugliese1,5,6 require different forms of immune interven-
of 8.2 ± 4.1 months, range 0–6 years). A large 1
Diabetes Research Institute, Leonard Miller tion to control each. This has profound
number of control specimens were examined, School of Medicine, University of Miami, importance in transplantation of these organs,
including 25 pancreases from adult patients Miami, FL, USA, 2Department of Surgery, particularly because simultaneous pancreas
with type 2 diabetes. Serial sections were Division of Transplantation, Leonard Miller and kidney transplantation is the procedure
stained for insulin, glucagon, enteroviral cap- School of Medicine, University of Miami, of choice for treatment of end stage renal
sid protein vp1, protein kinase R (PKR) Miami, FL, USA, 3Benaroya Research Institute, disease in individuals with T1D. It also offers
(which is unregulated in islets with enterovi- Seattle, WA, USA, 4Clinical Immunology, Am- important insights into evolving appropriate
rus infection), MHC class 1 and CD45. Dou- gen Inc., Seattle, WA, USA, 5Department of immune modulation strategies to interrupt
ble immunofluorescence staining was Microbiology and Immunology, Leonard Miller the T1D disease process, either for prevention
performed. Islets were classified as insulin- School of Medicine, University of Miami, or to sustain b-cell function in recent-onset
containing islets (ICIs), presumably residual Miami, FL, USA, 6Department of Medicine, T1D.
b-cells, or insulin-deficient islets (IDIs). (In Division of Endocrinology and Metabolism,
the T1D pancreases, 60% of islets are IDIs.) Leonard Miller School of Medicine, University Dimorphic histopathology of
Results: The majority (44 of 72, 61%) of of Miami, Miami, FL, USA
recent-onset T1D cases were positive for Diabetes 2010; 59: 947–57
long-standing childhood-onset
enteroviral vp1 antigen. Enteroviral capsid diabetes
protein vp1 immunostaining was restricted to
Background: Recurrent autoimmunity was R. Gianani,1 M. Campbell-Thompson,2
ICIs, and double immunofluorescence demon-
first described in pancreas transplants from S. A. Sarkar,1 C. Wasserfall,2 A. Pugliese,3
strated that this is restricted to b-cells. Other
identical twin donors, who did not need J. M. Solis,1 S. C. Kent,4 B. J. Hering,5
markers of infection (PKR, MHC-1) were also
immunosuppression to prevent graft rejec- E. West,1 A. Steck,1 S. Bonner-Weir,6
present. Enteroviral capsid protein vp1 was
tion. The current study explores the nature M. A. Atkinson,2 K. Coppieters,7
detected in a few cells in the pancreases of
of recurrent diabetes in pancreas–kidney M. von Herrath,7 G. S. Eisenbarth1
three of 39 (7.7%) non-diabetic paediatric
transplant recipients who were receiving 1
Barbara Davis Center for Childhood Diabe-
cases. A total of 40% of type 2 diabetic
immunosuppression therapy. tes, University of Colorado Denver, Aurora,
pancreases also stained for enteroviral capsid
Methods: In three patients with recurrent CO, USA, 2Department of Pathology, Univer-
protein vp1.
diabetes after pancreas–kidney transplanta- sity of Florida at Gainesville, Gainesville, FL,
Conclusions: Enterovirus staining is com-
tion, there was serial monitoring of antibodies USA, 3Diabetes Research Institute, Miami, FL,
mon in pancreases from recent-onset T1D.
and autoreactive T-lymphocytes, as well as USA, 4Center for Neurologic Diseases, Brigham,
Interestingly, it is also seen in some pancre-
pancreas biopsy. and Women’s Hospital Harvard Medical
ases from individuals with type 2 diabetes.
Results: Pancreas transplant biopsies were School, Boston, MA, USA, 5Schulze Diabetes
• Comment: These findings provide further
taken after hyperglycaemia recurrence and Institute, University of Minnesota, Minneapolis,
support for a potential role of enterovirus
revealed b-cell loss and insulitis, and no evi- MN, USA, 6Joslin Diabetes Center, Harvard
infection as an environmental factor leading
dence of graft rejection. From the time of Medical School, Boston, MA, USA, and
to T1D. There is a growing body of evidence
biopsy and on further follow-up, both anti- 7
La Jolla Institute for Allergy and Immunology,
supporting this concept, which is being stud-
bodies and autoreactive T-cells were repeat- La Jolla, CA, USA
ied in detail by the TEDDY Study Group (3).
edly demonstrated. Immune monitoring Diabetologia 2010; 53: 690–8
Identification of environmental factors that

ª 2011 Blackwell Publishing Ltd Int J Clin Pract, February 2011, 65 (Suppl. 170), 61–70
70 Immunomodulation

Background: Analysis of C-peptide in chil- tes. Although most patients had the expected blood injected into the pancreatic arterial sys-
dren characterised at diabetes onset for au- lack of b-cells and lack of C-peptide, 30% tem, and umbilical cord blood transfusion.
toantibodies shows heterogeneous showed persistent C-peptide, and these could The combination of low-dose cyclosporine
preservation of insulin secretion in long- be divided into two patterns. One pattern was and methotrexate in a very small pilot study
standing diabetes. This study sought to cha- consistent with classical type 1A diabetes pre- was impossible to interpret, and is unlikely to
racterise pancreases of childhood-onset diabe- sumably on an immune basis. The other pat- be pursued further anyway. That negative
tes in order to define the pathological basis of tern appeared to be totally different, with studies continue to dominate the field, and
that heterogeneity. normal-appearing islets, relatively high C-pep- that the positive ones still show decline in b-
Methods: Pancreases were evaluated from tide, absence of high risk HLA, and lack of cell function over time, has led to more calls
20 cadaveric organ pancreases from individu- antibodies at the time of death. All were said for combination approaches. When I have
als with childhood-onset (mean age of onset to have had the typical clinical appearance of advanced such prospects at meetings of paedi-
11.2 years, range 3–18 years) long-term T1D at the time of diagnosis. This suggests atric diabetologists, I hear groans. Yet when
(mean duration 14 years, range 1–35 years) that we still have a lot to learn about the evo- I have advanced these prospects at meetings
T1D. Pancreatic histology, islet autoantibodies lution of T1D, and that we need better tools of immunologists and transplant surgeons,
and C-peptide of patients were analysed. at diagnosis to better characterise individuals. I hear cheers. Hopefully, preclinical studies
Results: Most (70%) of the pancreases had This may prove to be particularly important will provide further guidance to support
only IDIs. C-peptide was not present in if we are to appropriately select patients with combination therapies, and hopefully regula-
patients lacking histological evidence of recent-onset T1D for newer immunological tory agencies will offer a path for evaluation
b-cells. Of six patients with extant b-cells, interventions, either in the context of clinical of these in human beings.
these could be divided into two patterns. In trials or for treatment when such agents are Meanwhile, a number of interesting studies
pattern A, there were mostly insulin-deficient approved by regulatory agencies. have offered further insights into the pathol-
islets (IDIs) and lobular retention of areas ogy and pathogenesis of T1D, the pathways
with ‘abnormal’ b-cells; islets retaining b-cells by which it may unfold, and how better to
contained survivin and enhanced HLA class 1, OVERALL COMMENTARY quantify who is at risk of developing T1D.
had low or no C-peptide, and were positive This year has been marked by a stunning These studies have also suggested that T1D is
for anti-islet autoantibody at time of death. number of papers relating to immune inter- not the same in everybody who appears to
In pattern B, none had IDIs, with all islets vention of T1D. Longer term observations develop it. And, perhaps most importantly,
containing normal-appearing but quantita- suggest that there may be sustained effects of that autoimmunity may not be able to be
tively reduced b-cells, without survivin or a short course of anti-CD3 monoclonal anti- addressed with the same therapeutic agents
HLA class 1; they were antibody-negative with body, which depletes T-lymphocytes and on that are used to prevent transplant rejection.
relatively high C-peptide, and lacked high risk recovery seems to favour regulatory T-lym- It has been a very exciting year, indeed.
HLA alleles. phocytes over effector T-lymphocytes. That
Conclusions: The data suggest that B-lymphocytes might be involved in T1D
C-peptide secretion in long-standing diabetic pathogenesis was suggested by positive results References
patients can be explained by two different from a trial with an anti-CD20 monoclonal 1 Couri CE, Oliveira MC, Stracieri AB et al. C-peptide levels
patterns of b-cell survival, one (pattern A) antibody, rituximab. There were also provoca- and insulin independence following autologous non-
that probably reflects autoimmune type 1A myeloablative haematopoietic stem cell transplantation in
tive observations from an extraordinarily tiny newly diagnosed type 1 diabetes mellitus. JAMA 2009; 301:
diabetes, and the other possibly reflecting a study with insulin B-chain given with IFA. 1573–9.
different subset of T1D. Yet, most intervention studies were negative – 2 TRIGR Study Group. Study design of the Trial to Reduce
• Comment: The investigators used pancre- IDDM in the Genetically at Risk (TRIGR). Pediatr Diabetes
mycophenolate mofetil given alone or in 2007; 8: 117–37.
ases collected by the JDRF nPOD (Network combination with daclizumab, low-dose diaz- 3 The TEDDY Study Group. The Environmental Determinants
for Pancreatic Organ Donors with Diabetes) oxide, vitamin D, an altered peptide ligand of of Diabetes in the Young (TEDDY) study: study design.
consortium to evaluate the histology of Pediatr Diabetes 2007; 8: 286–98.
insulin B (9–23), autologous bone marrow
patients with long-standing childhood diabe-

ª 2011 Blackwell Publishing Ltd Int J Clin Pract, February 2011, 65 (Suppl. 170), 61–70