Dr sumer yadavDr sumer yadav

IMMUNE SYSTEM - IMMUNE SYSTEM - INTRODUCTIONINTRODUCTION

COMPLEX SYSTEMCOMPLEX SYSTEM TWO-EDGED SWORDTWO-EDGED SWORD WORKS IN A TIERED FASHIONWORKS IN A TIERED FASHION

SIMPLE BARRIER FUNCTIONSIMPLE BARRIER FUNCTION SIMPLE NON SPECIFIC PHOGOCYTOSISSIMPLE NON SPECIFIC PHOGOCYTOSIS COMPLEX MECHANISMSCOMPLEX MECHANISMS

RECOGNISATION OF SELF / NON SELFRECOGNISATION OF SELF / NON SELF

CONT.CONT. BASIS OF DISTINGUISHING SELF FROM BASIS OF DISTINGUISHING SELF FROM

NON SELF: -NON SELF: - MAJOR / MINOR HISTOCOMPLATIBILTY MAJOR / MINOR HISTOCOMPLATIBILTY

ANTIGENS THAT ARE ENCODED BY ANTIGENS THAT ARE ENCODED BY MAJOR HISTOCOMPLATIBILTY COMPLEX MAJOR HISTOCOMPLATIBILTY COMPLEX (MHC) IN THEIR GENOME & EXPRESSED (MHC) IN THEIR GENOME & EXPRESSED AS HLA’S ON THEIR CELL MEMBRANE.AS HLA’S ON THEIR CELL MEMBRANE.

CLUSTERED ON SMALL SEGMENT OF CLUSTERED ON SMALL SEGMENT OF CHROMOSOME 6.CHROMOSOME 6.

BINDS PEPTIDE FRAGMENTS OF FOREIGN BINDS PEPTIDE FRAGMENTS OF FOREIGN PROTEINS FOR PRESENTATION TO PROTEINS FOR PRESENTATION TO ANTIGEN SPECIFIC T-CELLSANTIGEN SPECIFIC T-CELLS

CONT.CONT. FORMIDABLE BARRIER IN ORGAN FORMIDABLE BARRIER IN ORGAN

TRANSPLANTATIONTRANSPLANTATION HIGHLY PLEOMORPHICHIGHLY PLEOMORPHIC MHC GENES ARE – CLASSIFIED ASMHC GENES ARE – CLASSIFIED AS

CLASS - I CLASS - I ENCODE CELL SURFACE ENCODE CELL SURFACE CLASS – II CLASS – II GLYCOPROTEINS GLYCOPROTEINS

INVOLVED IN INVOLVED IN ANTIGEN ANTIGEN PRESENTATIONPRESENTATION

CLASS – III ENCODES COMPLEMENT CLASS – III ENCODES COMPLEMENT SYSTEMSYSTEM

CLASS – I MHCCLASS – I MHC EXPRESSED ON ALL EXPRESSED ON ALL

NUCLEATED CELLS / NUCLEATED CELLS / PLATELETSPLATELETS

THREE CLOSELY LINKED LOCITHREE CLOSELY LINKED LOCI HLA – AHLA – A HLA – BHLA – B HLA - CHLA - C

ENDOGENOUS ENDOGENOUS

CLASS – II MHCCLASS – II MHC CODED IN A REGION CALLED AS HLA DCODED IN A REGION CALLED AS HLA D

HLA – DPHLA – DP HLA – DQHLA – DQ HLA - DRHLA - DR

MORE SELECTIVELY EXPRESSED ON CELLS MORE SELECTIVELY EXPRESSED ON CELLS THAT ARE INVOLVED IN STIMULATING THAT ARE INVOLVED IN STIMULATING IMMUNE RESPONSE i.e. MACROPHAYES, IMMUNE RESPONSE i.e. MACROPHAYES, DENDRITE CELL, B CELL.DENDRITE CELL, B CELL.

EXPRESSION CAN BE INDUCED BY INJURYEXPRESSION CAN BE INDUCED BY INJURY PREDOMINANTLY PRESENTS EXOGENOUS PREDOMINANTLY PRESENTS EXOGENOUS

ANTIGENS AFTER ENDOCYTOSIS & PROCESSED ANTIGENS AFTER ENDOCYTOSIS & PROCESSED IN ENDOSOME/LYSOSOME IN ENDOSOME/LYSOSOME

CLASS – I MHCCLASS – I MHC EXPRESSED ON ALL EXPRESSED ON ALL

NUCLEATED CELLS / NUCLEATED CELLS / PLATELETSPLATELETS

THREE CLOSELY LINKED LOCITHREE CLOSELY LINKED LOCI HLA – AHLA – A HLA – BHLA – B HLA - CHLA - C

ENDROGENEOUS ENDROGENEOUS

ASSOCIATED OF HLA WITH ASSOCIATED OF HLA WITH DISEASES DISEASES

COMPONENTS OF IMMUNE COMPONENTS OF IMMUNE SYSTEMSYSTEM

HAEMATOPOIETIC STAM CELLS

MYELOID LYMPHOID

GRANULOCYTES MONONUCLEAR CELLS•T-LYMPHOCYTES•B-LYMPHOCYTES•N. K. CELLS

•NEUTROPHILS•EOSINOPHILS•BASOPHILES

•MONOCYTES•MACROPHAGES

DENDRITIC CELLSDENDRITIC CELLS MYELOID ORIGINMYELOID ORIGIN FINE NUMEROUS CYTOPLASMIC FINE NUMEROUS CYTOPLASMIC

PROCESSESPROCESSES MOST IMPORTANT APCMOST IMPORTANT APC CRUTIAL ROLE IN INITIATION OF ADAPTIVE CRUTIAL ROLE IN INITIATION OF ADAPTIVE

IMMUNE RESPONSEIMMUNE RESPONSE RIGHT LOCATION – RIGHT LOCATION –

UNDER EPITHELIUMUNDER EPITHELIUM IN INTERSTITUMIN INTERSTITUM

EXPRESSES MANY RECEPTORS FOR EXPRESSES MANY RECEPTORS FOR CAPTURING / RESPONDING TO MICROBES CAPTURING / RESPONDING TO MICROBES INCLUDING TLR’S MANNOSE RECEPTORS.INCLUDING TLR’S MANNOSE RECEPTORS.

T-LYMPHOCYTES: -T-LYMPHOCYTES: - ORIGINATE IN BONE MARROWORIGINATE IN BONE MARROW 60-70% - LYMPHOCYTES IN BLOOD60-70% - LYMPHOCYTES IN BLOOD IN PARACORTICAL AREAS OF L.N. & IN PARACORTICAL AREAS OF L.N. &

PERIARTERIOLAR SHEATHS OF SPLUNPERIARTERIOLAR SHEATHS OF SPLUN GENETICALLY PROGRAMMED TO RECOGNIZE GENETICALLY PROGRAMMED TO RECOGNIZE

A SPECIFIC CELL BOUND ANTIGEN BY A SPECIFIC CELL BOUND ANTIGEN BY MEANS OF AN ANTIGEN SPECIFIC T-CELL MEANS OF AN ANTIGEN SPECIFIC T-CELL RECEPTOR (TCR)RECEPTOR (TCR)

DIVIDED INDIVIDED IN T- HELPER-CD4 T- HELPER-CD4 TH1 – IL-2, IFN –TH1 – IL-2, IFN –

TH2 – IL-4, IL-5, IL-TH2 – IL-4, IL-5, IL-1313

T-CYTOTOXIC T-CYTOTOXIC CD8+CD8+

B - LYMPHOCYTESB - LYMPHOCYTES ARISE & MATURE IN BONE MARROWARISE & MATURE IN BONE MARROW 10-20% LYMPHOCYTES IN BLOOD10-20% LYMPHOCYTES IN BLOOD IN CORTEX OF L.N., WHITE PULP OF IN CORTEX OF L.N., WHITE PULP OF

SPLEENSPLEEN RECOGNIZE ANTIGEN VIA THE B CELL RECOGNIZE ANTIGEN VIA THE B CELL

ANTIGEN RECEPTOR COMPLEXANTIGEN RECEPTOR COMPLEX CAN BE ACTIVATED BY PROTEIN / NON CAN BE ACTIVATED BY PROTEIN / NON

PROTEIN ANTIGENPROTEIN ANTIGEN DIFFERENTIATES IN PLASMA CELLS – DIFFERENTIATES IN PLASMA CELLS –

ANTIBODIES ANTIBODIES

N. K. CELLSN. K. CELLS DO NOT EXPRESS SURFACE MOLECULESDO NOT EXPRESS SURFACE MOLECULES 10-15% OF PERIPHERAL BLOOD 10-15% OF PERIPHERAL BLOOD

LYMPHOCYTESLYMPHOCYTES POSSESS ACTIVATING RECEPTORS THAT POSSESS ACTIVATING RECEPTORS THAT

ARE CAPABLE OF RECOGNIZING ARE CAPABLE OF RECOGNIZING COMPLEMENT FRAGMENTS & ANTIBODIES COMPLEMENT FRAGMENTS & ANTIBODIES COATING THE TARGET CELL SURFACECOATING THE TARGET CELL SURFACE

ALSO POSSESS A RECEPTOR THAT INHIBITS ALSO POSSESS A RECEPTOR THAT INHIBITS ACTIVATION WHEN N. K. CELL COMES ACTIVATION WHEN N. K. CELL COMES INTO CONTACT WITH A SELF CELL. INTO CONTACT WITH A SELF CELL.

IMMUNE RESPONSE

INNATE ADAPTIVE

•MINOR THREATS•BARRIER / PHAGOCYTOSIS•COMPLEMENT ACTIVATION•DELAYS PROGRESSION

•FOR MAJOR THREETS•IMP. IN GRAFT REJECTION

FUNCTION OF IMMUNE FUNCTION OF IMMUNE SYSTEMSYSTEM

ADAPTIVE IMMUNE RESPONE

AFFERENT LIMB EFFERENT LIMB

AFFERENT LIMBAFFERENT LIMB FOR RECOGNITION OF ANTIGENFOR RECOGNITION OF ANTIGEN STARTS WITH INTERACTION BETWEEN AN APC STARTS WITH INTERACTION BETWEEN AN APC

AND TH-CELL.AND TH-CELL.STEPSSTEPS ANTIGEN TAKEN UP BY APCANTIGEN TAKEN UP BY APC PROCESSED INTO PEPTIDE FRAGMENTSPROCESSED INTO PEPTIDE FRAGMENTS FRAGMENTS ARE LOADED ONTO MHC CLASS II FRAGMENTS ARE LOADED ONTO MHC CLASS II

MOLECULES AND PRESENTED ON CELL SURFACEMOLECULES AND PRESENTED ON CELL SURFACE FOREIGN PEPTIDE & SELF MHC – RECOGNIZED BY T FOREIGN PEPTIDE & SELF MHC – RECOGNIZED BY T

CELL RECEPTOR.CELL RECEPTOR. BINDING OF COSTIMULATORY MOLECULES – BINDING OF COSTIMULATORY MOLECULES –

INCREASES CHANCES OF SUCCESSFUL INCREASES CHANCES OF SUCCESSFUL INTERACTION BUT APC & T-CELLINTERACTION BUT APC & T-CELL

SIGNAL TRANSDUCTION PATHWAY SIGNAL TRANSDUCTION PATHWAY

PRODUCTION OF TRANSCRIPTION PRODUCTION OF TRANSCRIPTION FACTORS FOR IL – 2/CYTOKINES FACTORS FOR IL – 2/CYTOKINES

IL – 2 IL – 2 TRANSLATED TRANSLATED RELEASEDRELEASED BINDS TO CD25 BINDS TO CD25

T-CELL PROLIFERATIONT-CELL PROLIFERATION

EFFERENT LIMBEFFERENT LIMB CONSTITUTES MULTIPLE POSSIBLE CONSTITUTES MULTIPLE POSSIBLE

EFFECTORS RESPONSE THAT CAN BE EFFECTORS RESPONSE THAT CAN BE ELICITED ONCE CD4 + CELLS ARE ELICITED ONCE CD4 + CELLS ARE ACTIVATEDACTIVATED

ACTIVATION – ACTIVATION –

GENERATION/ PROLIFERATION OF GENERATION/ PROLIFERATION OF CYTOTOXIC CD-8+T-CELLSCYTOTOXIC CD-8+T-CELLS

CYTOKINES(IL-2, IFN-γ, TNF-β)

CHEMOKINES

+

CD8+T-CELLS ALSO HAVE A T-CELL RECEPTOR CD8+T-CELLS ALSO HAVE A T-CELL RECEPTOR THAT IS CAPABLE OF RECOGNIZING FOREIGN THAT IS CAPABLE OF RECOGNIZING FOREIGN ANTIGEN IN THE CONTEXT OF SELF CLASS – I ANTIGEN IN THE CONTEXT OF SELF CLASS – I MHC.MHC.

ACTIVATION OF CD8+T-CELLS – CYTOTOXIC ACTIVATION OF CD8+T-CELLS – CYTOTOXIC SUBSTANCES (PERFORMING, GRARIZYME, TNF)SUBSTANCES (PERFORMING, GRARIZYME, TNF)

B-ALL – RECOGNIZES ANTIGEN – BINDS IT B-ALL – RECOGNIZES ANTIGEN – BINDS IT THROUGH B CELL RECEPTORTHROUGH B CELL RECEPTOR

BY RECEPTOR MEDIATED ENDOCYTOSIS - BY RECEPTOR MEDIATED ENDOCYTOSIS - INTERNALIZED PROCESSED INTO PEPTIDE INTERNALIZED PROCESSED INTO PEPTIDE FRAGMENTS FRAGMENTS

SIMULTANEOUSLY – CROSS LINKING WITH SIMULTANEOUSLY – CROSS LINKING WITH ANTIGEN AND B CELL ALSO UP-REGULATED ANTIGEN AND B CELL ALSO UP-REGULATED THE EXPRESSION OF MHC CLASS II MOLECULESTHE EXPRESSION OF MHC CLASS II MOLECULES

CYTOKINES B CELL PROLIFERATION

PLASMA CELLS

ANTIBODYPRODUCTION

COMPLEMENT ACTIVATION

ADCC

THE ALLOIMMUNE RESPONSETHE ALLOIMMUNE RESPONSE

FUNCTION OF IMMUNE RESPONSEFUNCTION OF IMMUNE RESPONSE REJECTION OF GRAFT IS MAINLY REJECTION OF GRAFT IS MAINLY

THROUGH T-CELLSTHROUGH T-CELLS BUTBUT

HUMORAL RESPONSEHUMORAL RESPONSE DELAYED TYPE HYPER SENSITIVITYDELAYED TYPE HYPER SENSITIVITY ADCCADCC EVEN INNATE IMMUNE RESPONSEEVEN INNATE IMMUNE RESPONSE

INDIRECT PATHWAYSINDIRECT PATHWAYS RECIPIENT T CELLS ARE CAPABLE OF RECIPIENT T CELLS ARE CAPABLE OF

RECOGNIZING RECOGNIZING FRAGMENTSFRAGMENTS OF OF DONOR MHC MOLECULES THAT DONOR MHC MOLECULES THAT HAVE BEEN PROCESSED BY APC OF HAVE BEEN PROCESSED BY APC OF RECIPIENT ORIGIN.RECIPIENT ORIGIN.

CLOSELY RESEMBLES THE RESPONSE CLOSELY RESEMBLES THE RESPONSE AGAINST ANY FOREIGN ANTIGEN.AGAINST ANY FOREIGN ANTIGEN.

SUBSERVIENT ROLE IN PRODUCING SUBSERVIENT ROLE IN PRODUCING ALLOIMMURU RESPONSE.ALLOIMMURU RESPONSE.

DIRECT PATHWAYDIRECT PATHWAY RECIPIENT T-CELLS ARE ALSO RECIPIENT T-CELLS ARE ALSO

CAPABLE OF DIRECTLY CAPABLE OF DIRECTLY RECOGNIZING RECOGNIZING INTACTINTACT DONOR DONOR MHC ON DONOR TISSUEMHC ON DONOR TISSUE

THIS MODE SEEMS TO DOMINATE THIS MODE SEEMS TO DOMINATE THE PROCESS OF EARLY THE PROCESS OF EARLY IMMUNOLOGIC ENGAGEMENT IMMUNOLOGIC ENGAGEMENT BETWEEN THE RECIPIENT AND BETWEEN THE RECIPIENT AND DONOR.DONOR.

INDIRECT DIRECT

TYPE OF REJECTIONTYPE OF REJECTION

HYPERACUTEHYPERACUTE ACUTEACUTE CHRONICCHRONIC

HYPERACUTEHYPERACUTE WITH IN FEW MTS. – HRS. – WITH IN FEW MTS. – HRS. –

SUDDEN ONSETSUDDEN ONSET CAUSESCAUSES

TRANSIENT PERIOD OF ISCHEMIATRANSIENT PERIOD OF ISCHEMIA COLD INJURYCOLD INJURY REPERFUSION INJURYREPERFUSION INJURY CYTOTOXIC ANTIBODIES DIRECTED CYTOTOXIC ANTIBODIES DIRECTED

AGAINST DONOR TISSUEAGAINST DONOR TISSUE

ISCHEMIA REPERFUSION INJURY ISCHEMIA REPERFUSION INJURY NECROSIS / APOPTOSIS OF DONOR CELLSNECROSIS / APOPTOSIS OF DONOR CELLS

ACTIVATION OF NK CELLS OF INNATE SYSTEM ACTIVATION OF NK CELLS OF INNATE SYSTEM BY STIMULATION OF THEIR BY STIMULATION OF THEIR TOLL - LIKE TOLL - LIKE RECEPTORRECEPTOR

CLINICALLY CLINICALLY SWELLING SWELLING DECREASED BLOOD FLOWDECREASED BLOOD FLOW DISCOLORATIONDISCOLORATION

MICROSCOPY – E/O ACCUMULATION OF MICROSCOPY – E/O ACCUMULATION OF PLATELETS / NEUTROPHILSPLATELETS / NEUTROPHILS

COMPLETELY REVERSIBLECOMPLETELY REVERSIBLE

ACUTE REJECTIONACUTE REJECTION WITH IN DAYS WEEKS UNTREATEDWITH IN DAYS WEEKS UNTREATED WITH IN MONTHS – OR YEARS WITH IN MONTHS – OR YEARS

TREATED / AFTER COMPLETIONTREATED / AFTER COMPLETION COMBINED PROCEDURE CELLULAR / COMBINED PROCEDURE CELLULAR /

HUMORAL TISSUE VASCULAR INJURYHUMORAL TISSUE VASCULAR INJURY MARKED BY AN INTERSTITIAL MARKED BY AN INTERSTITIAL

MONONUCLEAR CELL INFILTRATEMONONUCLEAR CELL INFILTRATE REVERSIBLE REVERSIBLE

CHRONIC REJECTIONCHRONIC REJECTION

OVER A PERIOD OF MONTH OVER A PERIOD OF MONTH YEAR WITH GRADUAL YEAR WITH GRADUAL PROGRESSIVE ONSETPROGRESSIVE ONSET

ANTIBODY DEPENDENT ANTIBODY DEPENDENT PHENOMENONPHENOMENON

IRREVERSIBLEIRREVERSIBLE

DIAGNOSIS OF GRAFT DIAGNOSIS OF GRAFT REJECTIONREJECTION

I – CLINICALI – CLINICAL II – BIOCHEMICALII – BIOCHEMICAL III – ALTERATIONS IN III – ALTERATIONS IN

CELLULAR/HUMMORAL IMMUNITYCELLULAR/HUMMORAL IMMUNITY

I – CLINICALI – CLINICAL GRAFT PALPATIONGRAFT PALPATION URINE VOLUME / PROTEINURIA / URINE VOLUME / PROTEINURIA /

HYPERTENSIONHYPERTENSION TEMPERATURETEMPERATURE

II – BIOCHEMICALII – BIOCHEMICAL RFT / LFTRFT / LFT

III – III – ALTERATIONS IN ALTERATIONS IN CELLULAR/HUMORAL IMMUNITYCELLULAR/HUMORAL IMMUNITY

CELLULARCELLULAR LOCAL SENSITIZATION OF THE LYMPHOID LOCAL SENSITIZATION OF THE LYMPHOID

CELL POPULATIONCELL POPULATION INCREASED IN BLAST CELL INCREASED IN BLAST CELL

TRANSFORMATIONTRANSFORMATION CAN BE STUDIED IN THE LYMPH NODES CAN BE STUDIED IN THE LYMPH NODES

DRAINING THE ORGAN / ORGAN / BLOODDRAINING THE ORGAN / ORGAN / BLOOD

METHODSMETHODS

LYMPHOBLAST ACTIVITY IN LYMPHOBLAST ACTIVITY IN PERIPHERAL BLOODPERIPHERAL BLOOD

MIXED LYMPHOCYTE MIXED LYMPHOCYTE CULTURECULTURE

LEUKOCYTE MIGRATION TESTLEUKOCYTE MIGRATION TEST LEUKOCYTE AGGREGATION LEUKOCYTE AGGREGATION

TESTTEST

HUMORALHUMORAL ANTIBODIES – NON SPECIFICANTIBODIES – NON SPECIFIC SERUM IMMUNOGLOBULINSSERUM IMMUNOGLOBULINS

IgG/IgM DECREASED DURING REJECTIONIgG/IgM DECREASED DURING REJECTION LITTLE VALUELITTLE VALUE

COMPLIMENT ACTIVATIONCOMPLIMENT ACTIVATION

TECHNIQUES FOR INCREASING GRAFT TECHNIQUES FOR INCREASING GRAFT SURVIVALSURVIVAL

I – TISSUE TYPINGI – TISSUE TYPING II – CROSS MATCH TYPINGII – CROSS MATCH TYPING III – IMMUNOSUPRESSIONIII – IMMUNOSUPRESSION IV - TOLERANCE IV - TOLERANCE

I – TISSUE TYPINGI – TISSUE TYPING IMMUNOLOGIC REACTION IN SOLID IMMUNOLOGIC REACTION IN SOLID

ORGAN TRANSPLANTATION IS ORGAN TRANSPLANTATION IS RESTRICTED IN ONE DIRECTION i.e. RESTRICTED IN ONE DIRECTION i.e. RECIPIENT AGAINST DONORRECIPIENT AGAINST DONOR

ONLY MHC MOLECULES THAT APPEAR ONLY MHC MOLECULES THAT APPEAR DIFFERENT TO RECIPIENTDIFFERENT TO RECIPIENT

TWO MHC CLASS I LOCI (A & B) AND ONE TWO MHC CLASS I LOCI (A & B) AND ONE MHC CLASS II LOCUS (DR) ARE ANALYZED MHC CLASS II LOCUS (DR) ARE ANALYZED ROUTINELY - PARTICULARLY IN TO ROUTINELY - PARTICULARLY IN TO KIDNEY & PANCREATIC ALLOGRAFTSKIDNEY & PANCREATIC ALLOGRAFTS

RETROSPECTIVE ANALYSIS – LIVER, RETROSPECTIVE ANALYSIS – LIVER, HEART, LUNG, INTESTINAL ALLOGRAFTS HEART, LUNG, INTESTINAL ALLOGRAFTS CAN BE TRANSPLANTED WITH OUT CAN BE TRANSPLANTED WITH OUT DEGREE OF MHC MISMATCH. DEGREE OF MHC MISMATCH.

II – CROSS MATCH TYPINGII – CROSS MATCH TYPING PREVIOUS ENCOUNTERS WITH CELLS THAT PREVIOUS ENCOUNTERS WITH CELLS THAT

POSSESS FOREIGN MHC ANTIGENS POSSESS FOREIGN MHC ANTIGENS B.T.B.T. PREGNANCYPREGNANCY PREVIOUS TRANSPLANTPREVIOUS TRANSPLANT

RE-EXPOSURE TO THAT ANTIGEN WILL RE-EXPOSURE TO THAT ANTIGEN WILL CAUSE HYPERACUTE REJECTIONCAUSE HYPERACUTE REJECTION

DONOR T AND B CELLS – INCUBATED WITH DONOR T AND B CELLS – INCUBATED WITH SERUM OF RECIPIENT SERUM OF RECIPIENT ANTIBODIES BIND ANTIBODIES BIND TO DONOR CELLSTO DONOR CELLS

ROUTINELY PERFORMED IN KIDNEY / ROUTINELY PERFORMED IN KIDNEY / PANCREATIC ALLOGRAFTSPANCREATIC ALLOGRAFTS

III – IMMUNOSUPRESSIONIII – IMMUNOSUPRESSION DRUGSDRUGS

ANTI-INFLAMMATORY AGENTS (NON-ANTI-INFLAMMATORY AGENTS (NON-SPECIFIC)SPECIFIC)

CORTICOSTEROIDCORTICOSTEROID CYTOSTATIC DRUGS (e.g. AZATHIOPRINE, CYTOSTATIC DRUGS (e.g. AZATHIOPRINE,

6-MP, CYCLOPHOSPHAMIDE)6-MP, CYCLOPHOSPHAMIDE) ANTI-LYMPHOCYTE GLOBULINSANTI-LYMPHOCYTE GLOBULINS

IONIZING RADIATION & RADIOMIMETIC IONIZING RADIATION & RADIOMIMETIC DRUGSDRUGS WHOLE BODY IRRITATIONWHOLE BODY IRRITATION LOCAL RADIATION – THYMUS, SPLEEN, LOCAL RADIATION – THYMUS, SPLEEN,

L.N.L.N.

SURGERYSURGERY L.N. REMOVALL.N. REMOVAL SPLENECTOMYSPLENECTOMY THYMECTOMYTHYMECTOMY

TYPES

INDUCTION MAINTENANCE

INDUCTION IMMUNO SUPPRESSIONINDUCTION IMMUNO SUPPRESSION

USE OF HIGH DOSE OF IMMUNO USE OF HIGH DOSE OF IMMUNO SUPPRESSANTS IN THE IMMEDIATE SUPPRESSANTS IN THE IMMEDIATE PERITRANSPLANTATION TIME.PERITRANSPLANTATION TIME.

MINIMIZE RISK OF REJECTION WHEN MINIMIZE RISK OF REJECTION WHEN THREAT IS GREATEST.THREAT IS GREATEST.

CONSISTS OF ADMINISTRATION OF CONSISTS OF ADMINISTRATION OF LYMPHOCYTE DEPLETING LYMPHOCYTE DEPLETING ANTIBODIESANTIBODIES MONOCLONAL / POLCLONALMONOCLONAL / POLCLONAL

MONOCLONAL ANTIBODIESMONOCLONAL ANTIBODIES OKT3OKT3

MOUSE IgG MONOCLONAL AB.MOUSE IgG MONOCLONAL AB. DIRECTED AGAINST DIRECTED AGAINST €€ CHAIN OF CD3 MEMBRANE CHAIN OF CD3 MEMBRANE

RECEPTOR OF T CELL – ALSO RESULTS IN RECEPTOR OF T CELL – ALSO RESULTS IN INTERNALIZATION OF RECEPTOR ANTIBODY INTERNALIZATION OF RECEPTOR ANTIBODY COMPLEX COMPLEX T-CELL NONFUNCTIONALT-CELL NONFUNCTIONAL

ALEMTUZUMAB ALEMTUZUMAB HUMANIZED MONOCLONAL ABHUMANIZED MONOCLONAL AB BINDING DOMAIN FOR CD52 i.e. EXPRESSED IN BINDING DOMAIN FOR CD52 i.e. EXPRESSED IN

ALL T & B – LYMPHOCYTES, MONOCYTES, ALL T & B – LYMPHOCYTES, MONOCYTES, MACROPHAGES, NK CELLS, DENDRITE CELLSMACROPHAGES, NK CELLS, DENDRITE CELLS

CAUSES LYMPHOCYTE DEPLETION BYCAUSES LYMPHOCYTE DEPLETION BY COMPLEMENT FIXATIONCOMPLEMENT FIXATION ADCCADCC GROWTH INHIBITION GROWTH INHIBITION

DACLIZUMAB / BASILIXIMABDACLIZUMAB / BASILIXIMAB MONOCLONAL AB TARGETED AGAINST MONOCLONAL AB TARGETED AGAINST αα CHAINS CHAINS

OF CD-25OF CD-25 NEW ARRIVALNEW ARRIVAL INHIBITS BINDING OF IL-2 TO CD 25INHIBITS BINDING OF IL-2 TO CD 25

MAINTENANCE IMMUNOSUPRESSIONMAINTENANCE IMMUNOSUPRESSION CONSISTS OF DRUG OR COMBINATION OF DRUGS CONSISTS OF DRUG OR COMBINATION OF DRUGS

USED USED CHRONICALLYCHRONICALLY TO PREVENT ALLOGRAFT TO PREVENT ALLOGRAFT REJECTIONREJECTION

CRUCIAL INITIAL STEPS OF IMMUNE RECOGNITION CRUCIAL INITIAL STEPS OF IMMUNE RECOGNITION & ATTACK ARE MEDIATED BY LYMPHOCYTES SO & ATTACK ARE MEDIATED BY LYMPHOCYTES SO MODERN IMMUNOSUPPRESSANT TARGET MODERN IMMUNOSUPPRESSANT TARGET PATHWAYS THAT ARE RESPONSIBLE FOR PATHWAYS THAT ARE RESPONSIBLE FOR LYMPHOCYTE ACTIVATION & PROLIFERATIONLYMPHOCYTE ACTIVATION & PROLIFERATION

ENGAGEMENT OF T CELL RECEPTOR WITH CO-ENGAGEMENT OF T CELL RECEPTOR WITH CO-STIMULATORY MOLECULES STIMULATORY MOLECULES SIGNAL SIGNAL TRANSDUCTION PATHWAYTRANSDUCTION PATHWAY IL-2 IL-2

REMOVAL OF PHOSPHATE GROUP FROM REMOVAL OF PHOSPHATE GROUP FROM CYTOPLASMIC NUCLEAR FACTOR OF CYTOPLASMIC NUCLEAR FACTOR OF ACTIVATED THYMOCYTES (NFAT) IS KEY ACTIVATED THYMOCYTES (NFAT) IS KEY STEP IN FORMATION OF IL-2.STEP IN FORMATION OF IL-2.

CYCLOSPORINE / TACROLIMUS INHIBITS CYCLOSPORINE / TACROLIMUS INHIBITS PHOSPHATASE ACTIVITY IF CALCINEURIN PHOSPHATASE ACTIVITY IF CALCINEURIN AFTER COMBINING WITH IMMUNOPHILLINS.AFTER COMBINING WITH IMMUNOPHILLINS.

ANTIPROLIFERATIVE AGENTSANTIPROLIFERATIVE AGENTS AZATHIOPRIHEAZATHIOPRIHE MYCOPHENOLETE MOFETIL (MMF)MYCOPHENOLETE MOFETIL (MMF) INHIBITS THE ENZYME 6-IONOSINE INHIBITS THE ENZYME 6-IONOSINE

MONOPHOSPHATE DEHYDROGENASE – KEY MONOPHOSPHATE DEHYDROGENASE – KEY ENZYME IN PURINE SYNTHESISENZYME IN PURINE SYNTHESIS

DEPLETION OF GUANAINE NUDEOTIDE IN DEPLETION OF GUANAINE NUDEOTIDE IN T/B CELLS T/B CELLS

SIROLIMUS : - BINDS TO IMMUNOPHILLIN SIROLIMUS : - BINDS TO IMMUNOPHILLIN – FROM COMPLEX– FROM COMPLEX INHIBITS INHIBITS ACTIVATION OF S6 KNASEACTIVATION OF S6 KNASEPREVENTS PROGRESSION OF CELL CYCLE PREVENTS PROGRESSION OF CELL CYCLE FROM G1 TO S PHASEFROM G1 TO S PHASE

BELATACEPT: - MONOCLONAL BELATACEPT: - MONOCLONAL ANTIBODY BLOCKS BINDING OF CD28 ANTIBODY BLOCKS BINDING OF CD28 WITH CD80 OR CD86WITH CD80 OR CD86 PREVENTS PREVENTS COSTIMULATION SIGNALS COSTIMULATION SIGNALS

POLYCLONAL –POLYCLONAL – ANTILYMPHOCYTE GLOBULINS: ANTILYMPHOCYTE GLOBULINS:

RABBIT ANTIHUMAN POLYCLONAL RABBIT ANTIHUMAN POLYCLONAL ANTI LYMPHOCYTE PREPARATIONANTI LYMPHOCYTE PREPARATION

ACTIONACTION COMPLEMENT MEDIATED LYSISCOMPLEMENT MEDIATED LYSIS ADCCADCC APOPTOSISAPOPTOSIS

COMPLICATIONS OF IMMUNOSUPRESSIONCOMPLICATIONS OF IMMUNOSUPRESSION ARISES AS UNIQUE PROPERTY OF THE AGENT ARISES AS UNIQUE PROPERTY OF THE AGENT

ITSELFITSELF DIRECT CONSEQUENCE OF IMMUNOSUPRESSIONDIRECT CONSEQUENCE OF IMMUNOSUPRESSIONCORTICOSTEROIDSCORTICOSTEROIDS FEATURES OF CUSHING SYNDROME WITH SALT & FEATURES OF CUSHING SYNDROME WITH SALT &

WATER RETENTIONWATER RETENTION HYPERTENSIONHYPERTENSION DIABETESDIABETES DISTORTION OF THE PHYSIOGNOMYDISTORTION OF THE PHYSIOGNOMY OSTEOPOROSISOSTEOPOROSIS AVN – DISABILITYAVN – DISABILITY GI ULCERATIONGI ULCERATION SEVERE SUDDEN HAEMORRHAGESSEVERE SUDDEN HAEMORRHAGES INCREASED SUSCEPTIBILITY TO INFECTIONINCREASED SUSCEPTIBILITY TO INFECTION RETARDATION OF WOUND HEALINGRETARDATION OF WOUND HEALING

CYTOTOXIC DRUGCYTOTOXIC DRUG WIDE VARIETYWIDE VARIETY ALOPECIA – SEVERE BONE MARROW ALOPECIA – SEVERE BONE MARROW

DEPRESSIONDEPRESSION RAPIDLY DIVIDING CELLS ARE AT MAJOR RAPIDLY DIVIDING CELLS ARE AT MAJOR

RISKRISKDUE TO IMMUNOSUPRESSIONDUE TO IMMUNOSUPRESSION DECREASED IN CELLULAR / HUMORAL DECREASED IN CELLULAR / HUMORAL

IMMUNITYIMMUNITY INCREASED NUMBER / VARIETY OF INCREASED NUMBER / VARIETY OF

INFECTION WITH INCLUDES BACTERIA INFECTION WITH INCLUDES BACTERIA (T.B./LEPROSY), FUNGI, PARASITIC (T.B./LEPROSY), FUNGI, PARASITIC NEMATODES & HELMITHS NEMATODES & HELMITHS

MALIGNANCY MALIGNANCY DANGER OF POTENTIATING DANGER OF POTENTIATING

MALIGNANCY.MALIGNANCY. NATURAL FUNCTION OF IMMUNITY IS NATURAL FUNCTION OF IMMUNITY IS

DETECTION & ELIMINATION OF DETECTION & ELIMINATION OF POTENTIAL MALIGNANT CLONES OF POTENTIAL MALIGNANT CLONES OF CELLS.CELLS.

DIRECT PROPORTIONALITY BETWEEN DIRECT PROPORTIONALITY BETWEEN EFFICACY OF IMMUNOSUPRESSION & EFFICACY OF IMMUNOSUPRESSION & THE FREQUENCY OF THIS DREADED THE FREQUENCY OF THIS DREADED COMPLICATION.COMPLICATION.

TOLERANCETOLERANCE STATE CHARACTERIZED BY THE SPECIFIC LACK OF STATE CHARACTERIZED BY THE SPECIFIC LACK OF

IMMUNEREACTIVITY, MAINTENANCE OF WHICH IMMUNEREACTIVITY, MAINTENANCE OF WHICH DOES NOT REQUIRE DOES NOT REQUIRE CHRONIC CHRONIC IMMUNOSUPRESSION.IMMUNOSUPRESSION.

RODENT MODEL STUDY RESULT ARE POSITIVE RODENT MODEL STUDY RESULT ARE POSITIVE CAN BE INDEED BY: -CAN BE INDEED BY: -

COSTIMULATION BLOCKADECOSTIMULATION BLOCKADE – OF CD28 IN – OF CD28 IN DIABETIC MICE RESULTED IN TOLERANCE TO DIABETIC MICE RESULTED IN TOLERANCE TO HUMAN PANCREATIC ISLETS.HUMAN PANCREATIC ISLETS.

BONE MARROW TRANSPLANTATIONBONE MARROW TRANSPLANTATION – – COMBINED WITH RADIATION, CHEMOTHERAPY COMBINED WITH RADIATION, CHEMOTHERAPY OR IMMUNOSUPRESSIONOR IMMUNOSUPRESSION

MORBITY/MORTALITY WITH B. M. MORBITY/MORTALITY WITH B. M. TRANSPLANTATIONTRANSPLANTATION

POTENT LYMPHOCYTES DEPLETING POTENT LYMPHOCYTES DEPLETING STRATEGIESSTRATEGIES

AT TIME OF TRANSPLANTATION.AT TIME OF TRANSPLANTATION. PRIMATES THAT WERE TREATED BY PRIMATES THAT WERE TREATED BY

ANTI CD3 IMMUNOTOXIN. ANTI CD3 IMMUNOTOXIN. DEMONSTRATED COMPLETE DEMONSTRATED COMPLETE TOLERANCE TO RENAL ALLOGRAFT.TOLERANCE TO RENAL ALLOGRAFT.

CHRONIC REJECTION WERE ALSO NOT CHRONIC REJECTION WERE ALSO NOT SEEN UPTO 5 YEARS.SEEN UPTO 5 YEARS.

FUTURE TRENDSFUTURE TRENDS MIXED HEMATOPOIETIC CHIMERISMMIXED HEMATOPOIETIC CHIMERISM

REQUIRE A BONE MARROW OR STEM CELL REQUIRE A BONE MARROW OR STEM CELL TRANSPLANT IN ADDITION TO ORGAN TRANSPLANT IN ADDITION TO ORGAN TRANSPLANT WITH MYELOABLATIVE TRANSPLANT WITH MYELOABLATIVE WHOLE BODY IRRADIATION TO ELIMINATE WHOLE BODY IRRADIATION TO ELIMINATE MATURE ALLOREACIVE T CELLSMATURE ALLOREACIVE T CELLS

CELLS FROM THE RECIPIENT & THE DONOR CELLS FROM THE RECIPIENT & THE DONOR CO-LOCATE TO THE THYMUS, ALL SELF CO-LOCATE TO THE THYMUS, ALL SELF REACTIVE & DONOR REACTIVE T-CELL ARE REACTIVE & DONOR REACTIVE T-CELL ARE ELIMINATED BY NEGATIVE SELECTIONELIMINATED BY NEGATIVE SELECTION

THE NEWLY DEVELOPING T-CELLS IN THE NEWLY DEVELOPING T-CELLS IN MIXED CHIMERAS ARE TOLERANT MIXED CHIMERAS ARE TOLERANT TOWARDS THE DONOR TOWARDS THE DONOR

CONT.CONT. NOW A DAYS NON-MYLOABLATINE NOW A DAYS NON-MYLOABLATINE

REGIMEN IS FOUND OUT THAT INCLUDE REGIMEN IS FOUND OUT THAT INCLUDE LIMITED WHOLE BODY IRRADIATION, LIMITED WHOLE BODY IRRADIATION, LOCAL THYMIC IRRADIATION, ANTI-LOCAL THYMIC IRRADIATION, ANTI-THYMOCYTE GLOBULIN, SPLENECTOMY, THYMOCYTE GLOBULIN, SPLENECTOMY, DONOR BONE MARROW CELL INFUSION DONOR BONE MARROW CELL INFUSION & 1 MONTH POST TRANSPLANT COURSE & 1 MONTH POST TRANSPLANT COURSE OF CYCLOSPORINE OF CYCLOSPORINE

DONOR THYMIC DONOR THYMIC TRANSPLANTATIONTRANSPLANTATION

ALLOGENIC THYMIC TISSUE WERE ALLOGENIC THYMIC TISSUE WERE SUCCESSFULLY SUCCESSFULLY COTTANSPLANTED AT THE TIME COTTANSPLANTED AT THE TIME OF ORGAN GRAFTINGOF ORGAN GRAFTING

IT WILL REDUCE DONOR SPECIFIC IT WILL REDUCE DONOR SPECIFIC TOLERANCE TOLERANCE

XENOTRANSPLANTATIONXENOTRANSPLANTATION

IF HUMAN RECIPIENT CAN BE PRE IF HUMAN RECIPIENT CAN BE PRE CONDITIONED IN SUCH A WAY AS CONDITIONED IN SUCH A WAY AS TO INDUCE IMMUNOLOGIC TO INDUCE IMMUNOLOGIC TOLERANCE TO THE XENOGRAFT TOLERANCE TO THE XENOGRAFT BYBY DONOR B.M. TRANSPLANTATIONDONOR B.M. TRANSPLANTATION GENE THERAPY GENE THERAPY

ADVANTAGE ADVANTAGE UNLIMITED SUPPLYUNLIMITED SUPPLY ISCHEMIC, COLD & REPERFUSION ISCHEMIC, COLD & REPERFUSION

INJURY CAN BE PREVENTEDINJURY CAN BE PREVENTED

hDAF TRANSGENIC SWINEhDAF TRANSGENIC SWINE hDAF OR CD55 (DECAY ACCELERATING hDAF OR CD55 (DECAY ACCELERATING

FACTOR)FACTOR) CD59CD59

MEMBRANE GLYCOPROTEINS IN HUMAN MEMBRANE GLYCOPROTEINS IN HUMAN COMPLEMENT CASCADE THAT ACT AS COMPLEMENT CASCADE THAT ACT AS INHIBITORS IN PATHWAYS & ACTIVATION INHIBITORS IN PATHWAYS & ACTIVATION OF BOTH PATHWAYS MAY BE HALTEDOF BOTH PATHWAYS MAY BE HALTED

TRANSGENIC SWINE – EXPRESS hDAF & h TRANSGENIC SWINE – EXPRESS hDAF & h CD59 PROTEINS ON THEIR VASCULAR CD59 PROTEINS ON THEIR VASCULAR ENDOTHELIUM ENDOTHELIUM

CLONED CLONED αα1, 3-GAL KNOK OUT PIGS1, 3-GAL KNOK OUT PIGS HYPERACUTE REJECTION IS DUE TO ANTI HYPERACUTE REJECTION IS DUE TO ANTI αα-GAL -GAL

RESPONSES.RESPONSES. PIGS ARE PRODUCED IN WHICH GENE THAT PIGS ARE PRODUCED IN WHICH GENE THAT

ENCODES FOR ENCODES FOR αα 1, 3 GT ENZYME THAT IS 1, 3 GT ENZYME THAT IS NECESSARY FOR GENERATION OF NECESSARY FOR GENERATION OF αα GAL GAL EPITOPES IS KNOCKED OUT, THEORETICALLY EPITOPES IS KNOCKED OUT, THEORETICALLY LEAVING NO TARGET FOR HUMAN ANTI LEAVING NO TARGET FOR HUMAN ANTI αα GAL GAL ANTIBODIESANTIBODIES

YAMDA & COWORKERS BY USING RENAL YAMDA & COWORKERS BY USING RENAL XENOGRAFT FROM SUCH A CLONED PIG – XENOGRAFT FROM SUCH A CLONED PIG – TRANSPLANTED IN NON HUMAN PRIMATES TRANSPLANTED IN NON HUMAN PRIMATES WITH COTRANSPLANTATION OF WITH COTRANSPLANTATION OF VASCULARISED DONOR THYMUS REPORTED VASCULARISED DONOR THYMUS REPORTED HEALTHY FUNCTIONAL XENOGRAFT SURVIVAL HEALTHY FUNCTIONAL XENOGRAFT SURVIVAL OF 3 MONTHS. OF 3 MONTHS.