AUTOIMMUNITY AND IMMUNOLOGICAL ASPECTS OF TRANSPLATATION

AUTOIMMUNITY
INAPPROPRIATE IMMUNE RESPONSE TO SELF ANTIGENS. SELF TOLERENCE 1.CLONAL DELETION OF ALL SELF REACTIVE B AND T CELLS DURING THEIR DEVELOPMENT 2.CLONAL ANERGY OF SELF REACTING LYMPHOCYTES

MECHANISMS OF DEVELOPMENT OF AUTOIMMUNITY

RELEASE OF SEQUESTERED ANTIGENS MOLECULAR MIMICRY INAPPROPRIATE MHC-II EXPRESSION POLYCLONAL ACTIVATION OF B-CELLS

RELEASE OF SEQUESTERED ANTIGENS

RELEASE OF SPERMS AFTER VASECTOMY LENS PROTEINS AFTER EYE DAMAGE MYELIN BASIC PROTEIN(MBP)- CAUSE MULTIPLE SCLEROSIS DIRECT MBP INJECTION IN EXPERIMENTAL ANIMALS EXPERIMENTAL AUTOIMMUNE ENCEPHLITIS(EAE)

MOLECULAR MIMICRY
SHARING OF EPITOPES BETWEEN AN INFECTIOUS AGENT AND ITS HOST.

ANTIBODIES DIRECTED AGAINST THE INFECTIOUS AGENTS STARTS REACTING WITH SELF AG.

TRIGGERS AUTOIMMUNITY.

MOLECULAR MIMICRY BETWEEN PROTEINS OF INFECTIOUS ORGANISMS AND HOST

PROTEIN ANTIGEN RESIDUE NO 1.POLIO VIRUS ACETYLCHOLINE RECEPTOR 2.RABIES VIRUS INSULIN RECEPTOR 3. HIV-p24 IgG 4. MEASLES VIRUS CORTICOTROPIN
70 176

SEQUENCE
KESRTG KESTRG

147 764 160 466 13 18

KESLVI KESLVI GEVTTT GEVTTT LECIRA LECIRA

 ANTIBODIES TO STREPTOCOCCAL BACTERIAL ANTIGENS CROSS REACT WITH HEART MUSCLE ANTIGEN- CAUSE RHEUMATIC FEVER POST RABIES VACCINATION ENCEPHALITIS VACCINE MADE BY GROWING RABIES VIRUS IN RABBIT BRAIN RABBIT BRAIN INDUCE ANTIBODY IN VACCINATED PERSON CROSS REACT WITH HUMAN BRAIN

INAPPROPRIATE MHC-II EXPRESSION

EXPRESSION OF MHC ON NON APCs SENSITIZATION OF TH CELLS ON HOST PROTEINS AUTOIMMUNITY

TRAUMA OR VIRAL INFECTION INFLAMMATORY RESPONSE INCREASED IFN- INDUCE HIGH MHC-II EXPRESSION ON NON APC INAPPROPRIATE THCELL ACTIVATION IDDM-BETA CELLS EXPRESS HIGH LEVELS OF MHC-I AND MHC-II

POLYCLONAL ACTIVATION OF B-CELLS

POLYCLONAL ACTIVATORS-EBV,CMV,G-ve BACT STIMULATE B- CELLS REACTIVE TO SELF ANTIGEN Eg INFECTIOUS MONONUCLEOSIS-AUTO ANTIBODIES AGAINST T-CELLS,B-CELLS, NUCLEAR COMPONENTS AIDS-AUTO ANTIBODIES TO RBCs, PLATELETS

TYPES OF AUTOIMMUNE DISEASE

1. ORGAN SPECIFIC DISEASE 2. GENERALISED SYSTEMIC DISEASE

1. ORGAN-SPECIFIC
TARGET IS A MOLECULE UNIQUE TO THAT ORGAN

a) DISEASE CAUSED BY CELLULAR DAMAGE

HASHIMOTOS THYROIDITIS T CELL AND ANTIBODY MEDIATED AGAINST THYROGLOBULIN AND THYROID PEROXIDASE DECREASED IODINE UPTAKE HYPOTHYROIDISM AND GOITRE

GOODPASTURES SYNDROME ANTIBODIES TO MEMBRANE ANTIGENS IN KIDNEY AND ALVEOLI COMPLEMENT ACTIVATION, CELL DAMAGE, INFLAMMATION IDDM (INSULIN-DEPENDENT DIABETES MELLITUS) BOTH T AND B CELLS INVOLVED CTLS, AUTOANTIBODIES SUBSEQUENT DTH RESPONSE KILLS BETA CELLS

 HAEMOLYTIC ANAEMIA a) PERNICIOUS ANAEMIA-AUTOANTIBODIES AGAINST INTRINSIC FACTOR b) AUTOIMMUNE HAEMOLYTIC ANAEMIA-Abs AGAINST RBCs SURFACE ANTIGENS c) DRUG INDUCED HAEMOLYTIC ANAEMIAPENICILLINE, METHYLDOPA BIND TO RBC AND MAKE THEM ANTIGENIC

b) ANTIBODIES AS AGONIST OR ANTAGONIST TO RECEPTORS GRAVES DISEASE AUTOANTIBODY TO TSH RECEPTOR LEADS TO CONSTANT THYROID STIMULATION

 MYASTHENIA GRAVIS
AUTOANTIBODY BLOCKS ACH RECEPTOR BLOCK NORMAL TRANSMISSION OF NERVE IMPULSE EVENTUALLY DESTROYS IT

SYSTEMIC AUTOIMMUNE DISEASE

TISSUE DAMAGE WIDESPREAD AGAINST WIDELY PRESENT ANTIGENS LIKE RBCs, PLATELETS, DNA, MYELIN, CONNECTIVE TISSUE DEFECT OF IMMUNE REGULATION MORE COMMON IN FEMALES

SYSTEMIC LUPUS ERYTHEMATOSUS(SLE)

10 TIMES MORE IN FEMALE AUTOANTIBODIES AGAINST WIDELY PRESENT CELLS LIKE RBC, PLATELETS, DNA, HISTONES, CLOTTING FACTORS, LEUKOCYTES. Ag-Ab COMPLEX ACTIVATE COMPLEMENT SYSTEM

SIGN AND SYMPTOMS OF SLE

SLE

MULTIPLE SCLEROSIS(MS)
AUTOREACTIVE T CELLS TO MYELIN SHEATH WIDESPREAD INFLAMMATORY LESION ALONG NERVES GROSS NEUROLOGICAL DYSFUNCTION

RHEUMATOID ARTHRITIS
IgM ANTIBODIES AGAINST IgG IgG-IgM COMPLEX DEPOSITED IN JOINTS CHRONIC AND PROGRESSIVE JOINT DISEASE ALSO INVOLVE HAEMATOLOGICAL , CVS,RESPIRATORY ORGANS

TREATMENT OF AUTOIMMUNE DISEASE

I. CURRENT THERAPIES - AIMED AT REDUCING SYMPOTMS BY PROVIDING NON SPECIFIC SUPPRESSION OF IMMUNE SYSTEM II. EXPERIMENTAL THERAPEUTICAL APPROCHES- TRY TO INDUCE SPECIFIC IMMUNITY

I. CURRENT THERAPIES
IMMUNOSUPPRESSIVE DRUGS - CORTICOSTEROIDS, AZATHIOPRINE - SLOWS THE PROLIFERATION OF LYMPHOCYTES -GENERAL REDUCTION IN IMMUNE RESPONSE CYCLOSPORIN A - BLOCKS SIGNAL TRANSDUCTION MEDIATED BY THE TCR (INHIBITS ONLY ANTIGEN-ACTIVATED T CELLS WHILE SPARING NON-ACTIVATED ONES)
26

 THYMECTOMY - REMOVAL OF THYMUS FROM PATIENTS WITH MYASTHENIA GRAVIS PLASMAPHERESIS - REMOVES ANTIGEN-ANTIBODY COMPLEXES FOR A SHORT- TERM REDUCTION IN SYMPTOMS USED IN GRAVES DISEASE, MYASTHENIA GRAVIS, SLE

II. EXPERIMENTAL THERAPEUTIC

APPROACHES
PEPTIDE BLOCKADE OF MHC MOLECULES -USED WHEN SEQUENCE OF AUTO ANTIGEN IS KNOWN - A SYNTHETIC PEPTIDE IS USED TO BIND IN PLACE OF THE REGULAR PEPTIDE ON THE MHC - INDUCES A STATE OF CLONAL ANERGY IN THE AUTOIMMUNE T-CELLS
28

 MONOCLONAL ANTIBODY TREATMENT

-ANTI CD4 -BLOCK ALL TH CELLS - ANTI IL-2 RECEPTOR -BLOCKS ACTIVATED THCELLS - AGAINST AND CHAINS OF TCRS - AGAINST MHC MOLECULE

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IMMUNOLOGICAL ASPECTS OF TRANSPLANTATION

TRANSFER OF CELLS, TISSUES OR ORGANS FROM ONE SITE TO ANOTHER. TRANSPLANTED CELL, TISSUE AND ORGAN IS CALLED GRAFT.

TYPES OF GRAFTS
AUTOGRAFT- WITHIN SAME INDIVIDUAL ISOGRAFT- FROM GENETICALLY IDENTICAL DONOR

ALLOGRAFT- FROM GENETICALLY DIFFERENT MEMBER OF THE SAME SPECIES

XENOGRAFT- FROM A DIFFERENT SPECIES

Ch. 17

IMMUNE RESPONSE TO GRAFT

ACCEPTANCE OR REJECTION OF A GRAFT DEPEND ON ANTIGENIC AND GENETIC MAKEUP. ANY GRAFT PERCEIVED AS FOREIGN IS TARGETED TO BE DESTROTED AND REJECTED.

FIRST AND SECOND SET REJECTION

 GRAFT HISTOCOMPATIBILITY ANTIGENICALLY SIMILAR GRAFTS; USUALLY ACCEPTED GRAFT HISTOINCOMPATIBILITY SIGNIFICANT ANTIGENIC DIFFERENCE; REJECTED HISTOCOMPATIBILITY DETERMINED BY TWO ANTIGENS1. BLOOD GROUP ANTIGEN 2. MHC ANTIGEN

TISSUE TYPING
IDENTIFICATION AND MATCHING OF BLOOD GROUP AND HLA ANTIGENS BETWEEN DONOR AND RECIEPIENT 1. BLOOD GROUP ANTIGENS- EXPRESSED ON RBCs, ENDOTHELIAL AND EPITHELIAL CELLS.

2.HLA TYPING

p. 429

Ch. 17

MECHANISM OF GRAFT REJECTION

BASICALLY A CELLULAR IMMUNE RESPONSE INVOLVING CELL MEDIATED CYTOTOXICITY AND DTH REJECTION INVOLVES TWO STAGES1. SENSITIZATION STAGE 2. EFFECTOR STAGE

SENSITIZATION STAGE
ALLOANTIGENS ON GRAFT ARE RECOGNIZED BY HOST T CELLS APCs PROCESS AND PRESENT ANTIGEN IN ASSOCIATION WITH MHC TO TH AND TC CELLS. TH ACTIVATION TH1 RESPONSECONVERTS TC CELL INTO CTLs AND MEMORY CELLS. EFFECTOR RESPONSE

EFFECTOR STAGE
ACTUAL CELLULAR IMMUNE RESPONSE OCCURS INFILTRATION OF GRAFT TISSUE BY T CELLS AND MACROPHAGES LIKE DTH PREDOMINANTLY CELL MEDIATED CYTOTOXICITY AND DTH ADCC & COMPLEMENT MEDIATED CELL LYSIS ALSO CONTRIBUTE

p. 432

Ch. 17

TYPES OF GRAFT REJECTION

HYPERACUTE REJECTION ACUTE REJECTION CHRONIC REJECTION

HYPERACUTE REJECTION
WITHIN 24 HOURS BEFORE VASCULARIZATION OF GRAFT TISSUE BY PRE-EXISTING ANTIBODIES -REPEATED BLOOD TRASFUSION -REPEATED PREGNANCIES -PREVIOUS TRANSPLANT

AVASCULAR NECROSIS IN HYPERACUTE REJECTION

ACUTE- WITHIN A FEW WEEKS TH CELL ACTIVATION CHRONIC- A LONG TIME LATER HUMORAL AND CELL-MEDIATED

Ch. 17

IMMUNOSUPPRESSIVE THERAPY
A.GENERALIZED IMMUNOSUPPRESSION THERAPY OTHER RAPIDLY-DIVIDING CELLS ARE AFFECTED (EPITHELIAL CELLS, BONE MARROW CELLS)

1.MITOTIC INHIBITORS- AZATHIOPRINE, METHOTREXATE BLOCK SYNTHESIS OF INOSINIC ACID DIMNISHES THE SYNTHESIS OF RAPIDLY . DIVIDING CELLS INCLUDING T AND B CELLS
Ch. 17

2.CORTICOSTEROIDS- ANTI-INFLAMMATORY
CAUSE LYMPHOLYSIS DECREASES T-CELL ACTIVATION BY INHIBITING NF-kB REDUCES PHAGOCYTIC ACTIVITY OF MACROPHAGES

3.CYCLOSPORINE(CsA) CALCINEURIN NF-ATc

CsA-IMMUNOPH YLIN

NF-AT (DNA BINDING PROTEIN)

GENE TRANSCRIPTION OF IL-2&IL-2R

ACTIVATION OF RESTING T CELLS

RAPAMYCIN-INHIBITS ACTIVATED TH CELLS

4.TLI- TOTAL LYMPHOID IRRADIATION

IN BONE MARROW TRANSPLANTATION

RECIPIENTS LYMPHOID TISSUES ARE IRRADIATED

BEFORE GRAFTING BONE MARROW IS NOT IRRADIATED, TRANSPLANTED LYMPHOID CELLS PROLIFERATE AND RENEW THE CIRCULATING LYMPHOCYTES

Ch. 17

B.SPECIFIC IMMUNOSUPPRESSION
MONOCLONAL ANTIBODIES ARE USED

1.REDUCTION OF MATURE TCELLS

MONOCLONAL ANTIBODIES BLOCKS -CD3 COMPLEX OF TCR -IL-2R -CD-4 -ADHESION MOLECULES-ICAM 1 &LFA-7
Ch. 17

2. BLOCKING CO-STIMULATORY SIGNALS SIGNAL MEDIATED BY B7(APC) INTERACTION WITH CD28&CTLA-4(TH CELLS)

CTLA-4 Ig INFUSION PROTEIN- BLOCKS CO STIMULATORY SIGNALS