IMMUNOLOGY OF TRANSPLANTATION

IMMUNOLOGY OF IMMUNOLOGY OF TRANSPLANTATIONTRANSPLANTATION

Lecture 7Lecture 7

2013/20142013/2014

Jan Jan ŻeromskiŻeromski

POINTS TO BE DISCUSSEDPOINTS TO BE DISCUSSED

Immunogenetics – basic factsImmunogenetics – basic factsHistocompatibility antigens and their role in Histocompatibility antigens and their role in transplantationtransplantationTypes of grafts, including fetusTypes of grafts, including fetusMechanisms of graft rejectionMechanisms of graft rejectionThe tempo of rejectionThe tempo of rejectionPrevention of rejectionPrevention of rejectionGraft versus host reactionGraft versus host reaction

MAJOR HISTOCOMPATIBILITY MAJOR HISTOCOMPATIBILITY COMPLEX (MHC)COMPLEX (MHC)

Is located on short arm of chromosome 6Is located on short arm of chromosome 6 It includes 3 regionsIt includes 3 regions: class Ia: class Ia (loci A, B, C) (loci A, B, C)

class Ibclass Ib (loci E, F, G, H), (loci E, F, G, H), class IIclass II (loci DR, DQ, (loci DR, DQ, DP) and DP) and class IIIclass III

Genes of class Ia and class II are highly Genes of class Ia and class II are highly polymorphic, while those of class Ib and class polymorphic, while those of class Ib and class III are notIII are not

Polymorphism means occurence of several Polymorphism means occurence of several allelles ie.genes allelles ie.genes enencoding various MHC coding various MHC antigens located at the same locusantigens located at the same locus

MAJOR HISTOCOMPATIBILITY MAJOR HISTOCOMPATIBILITY ANTIGENSANTIGENS

Histocompatibility antigens are cell surface Histocompatibility antigens are cell surface

expressed on all cells (class I) and on APC, expressed on all cells (class I) and on APC,

B cells, monocytes/macrophages (class II)B cells, monocytes/macrophages (class II)

They are targets for rejectionThey are targets for rejection

They are inherited from both parents as MHC They are inherited from both parents as MHC

haplotypes and are co-dominantly expressedhaplotypes and are co-dominantly expressed

MINOR HISTOCOMPATIBILITY MINOR HISTOCOMPATIBILITY ANTIGENSANTIGENS

They also participate in rejection but to lesser They also participate in rejection but to lesser degreedegree

Disparity of several minor antigens may result Disparity of several minor antigens may result in rejection, even when MHC antigens are in rejection, even when MHC antigens are concordant between donor and recipientconcordant between donor and recipient

They include blood group antigens, tissue They include blood group antigens, tissue and organ antigens, normal cellular and organ antigens, normal cellular constituentsconstituents

They are peptides derived from polymorphic They are peptides derived from polymorphic cellular proteins bound to MHC class I moleculescellular proteins bound to MHC class I molecules

TYPES OF GRAFTSTYPES OF GRAFTS

Autologous graft (autograft)Autologous graft (autograft) – in the same – in the same individual: from one site to another oneindividual: from one site to another one

Isogenic (isograft)Isogenic (isograft) – between genetically – between genetically identical individualsidentical individuals

Allogeneic (allograft or homograft)Allogeneic (allograft or homograft) – between – between different members of the same speciesdifferent members of the same species

Xenogeneic (xenograft)Xenogeneic (xenograft) – between mmbers of – between mmbers of different speciesdifferent species

MECHANISMS OF REJECTIONMECHANISMS OF REJECTION

Depend on disparity of genetic background Depend on disparity of genetic background between donor and recipientbetween donor and recipientT cells are critical in graft rejectionT cells are critical in graft rejectionRejection responses in molecular terms, are due Rejection responses in molecular terms, are due to TCR-MHC interactionto TCR-MHC interactionGraft and host MHC molecules present different Graft and host MHC molecules present different peptidespeptidesDifferent MHC molecules have different peptide-Different MHC molecules have different peptide-binding groovesbinding groovesT lymphocytes can directly recognize and T lymphocytes can directly recognize and respond to foreign MHC moleculesrespond to foreign MHC molecules

ALLOREACTIVE CELLS ARE SO ALLOREACTIVE CELLS ARE SO COMMON, BECAUSE:COMMON, BECAUSE:

Foreign MHC molecules differ from self MHC at Foreign MHC molecules differ from self MHC at

multiple different aminoacid residues, each of multiple different aminoacid residues, each of

which may produce determinant recognized by which may produce determinant recognized by

a different cross-reactive T cell clonea different cross-reactive T cell clone

Thus, each foreign MHC molecule is recognized Thus, each foreign MHC molecule is recognized

by multiple clones of T cellsby multiple clones of T cells

2% of host T cells are capable recognizing and 2% of host T cells are capable recognizing and

responding to a single MHC foreign moleculeresponding to a single MHC foreign molecule

TEMPO OF REJECTIONTEMPO OF REJECTION

Hyperacute rejectionHyperacute rejection antibodies to HLA and ABO blood group system antibodies to HLA and ABO blood group system (hours or first days)(hours or first days)

Acute rejectionAcute rejection T cells (days or weeks)T cells (days or weeks)

Chronic rejectionChronic rejection various mechanisms: cell-mediated, deposition various mechanisms: cell-mediated, deposition of antibodies or antigen antibody complexes with of antibodies or antigen antibody complexes with subsequent obliteration of blood vessels and subsequent obliteration of blood vessels and interstitial fibrosis (months or years)interstitial fibrosis (months or years)

THE MODE OF ACTION OF ANTIBODIES THE MODE OF ACTION OF ANTIBODIES IN TRANSPLANT REJECTIONIN TRANSPLANT REJECTION

By damage of endothelial cells due to activation By damage of endothelial cells due to activation

of complementof complement

By induction of ADCC reactionBy induction of ADCC reaction

Through intensification of inflammatory reaction Through intensification of inflammatory reaction

by the release of complement componentsby the release of complement components

(C3a, C5a) (C3a, C5a)

By activation of clotting systemBy activation of clotting system

VARIABLES DETERMINING VARIABLES DETERMINING TRANSPLANT OUTCOMETRANSPLANT OUTCOME

Donor-host antigenic disparityDonor-host antigenic disparity

Strength of host anti donor responseStrength of host anti donor response

Immunosuppressive regimenImmunosuppressive regimen

The condition of the allograftThe condition of the allograft

Primary disease of the hostPrimary disease of the host

PATHOGENESIS OF CHRONIC PATHOGENESIS OF CHRONIC REJECTIONREJECTION

Is the result of organ damage by Is the result of organ damage by immunologic and non-immunologic factorsimmunologic and non-immunologic factors

Initially – the minor damage and activation Initially – the minor damage and activation of endothelium by cytotoxic T cells and of endothelium by cytotoxic T cells and antibodiesantibodies

PATHOGENESIS OF CHRONIC PATHOGENESIS OF CHRONIC REJECTIONREJECTION -2 -2

Production by endothelial cells biologically active Production by endothelial cells biologically active mediators (PDGF, PAF, TNF, thromboxans etc.)mediators (PDGF, PAF, TNF, thromboxans etc.)

Secretion of cytokines by infiltrating lymphocytesSecretion of cytokines by infiltrating lymphocytes

Mitogenic effect on myocytes and fibroblasts Mitogenic effect on myocytes and fibroblasts results in cell proliferation and fibrosisresults in cell proliferation and fibrosis

CHRONIC REJECTION IS MORE CHRONIC REJECTION IS MORE FREQUENT WHEN:FREQUENT WHEN:

Were previous epiWere previous epissodes of acute rejectionodes of acute rejection

There is a low number of compatible HLA There is a low number of compatible HLA antigens with recipientantigens with recipient

PatientPatient on on inadequate immunosuppression inadequate immunosuppression

Recipient is hypertonicRecipient is hypertonic

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CHRONIC REJECTION IS CHRONIC REJECTION IS MORE FREQUENT WHEN:MORE FREQUENT WHEN:

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In the case of cytomegaly virus infectionIn the case of cytomegaly virus infection

The period of organ storage was too longThe period of organ storage was too long

Patient is heavy smoker and/or is hyperlipidemicPatient is heavy smoker and/or is hyperlipidemic

Organ mass is unproportionally small as Organ mass is unproportionally small as

compared to body masscompared to body mass

MODERN IMMUNOSUPPRESSIVE MODERN IMMUNOSUPPRESSIVE THERAPYTHERAPY

CCyyclosporinclosporin (CsA), (CsA), TacrolimusTacrolimus (FK-506) – inhibit IL-2 (FK-506) – inhibit IL-2 production by T cellsproduction by T cells calcineurin antagonistcalcineurin antagonist

Sirolimus (rapamycinSirolimus (rapamycin) – inhibits ) – inhibits signals transmitted by signals transmitted by IL-2 binding to IL-2RIL-2 binding to IL-2R (antiproliferating effect) (antiproliferating effect)

AzathioprineAzathioprine – reduces numbers and function both, T – reduces numbers and function both, T and B cells, by inhibition of purine metabolismand B cells, by inhibition of purine metabolism

MODERN IMMUNOSUPPRESSIVE MODERN IMMUNOSUPPRESSIVE THERAPYTHERAPY -2 -2

Mycophenolate mofetilMycophenolate mofetil (MMF) – inhibits DNA (MMF) – inhibits DNA synthesis and protein glycosylationsynthesis and protein glycosylation, supresses , supresses expression of CD25, -71, -154, -28.expression of CD25, -71, -154, -28.

Anti-IL-Anti-IL-2 monoclonal antibodies2 monoclonal antibodies

FTY 720FTY 720 – dramatic effect on lymphocyte – dramatic effect on lymphocyte migrationmigration

GRAFT VERSUS HOST DISEASE (GVH)GRAFT VERSUS HOST DISEASE (GVH)

Is common complication in recipients of Is common complication in recipients of bone marrow transplantsbone marrow transplants

Is due to the presence of alloreactive T Is due to the presence of alloreactive T cells in the graftcells in the graft

It results in severe tissue damage, It results in severe tissue damage, particularly to the skin and intestineparticularly to the skin and intestine

GRAFT VERSUS HOST DISEASE (GVH)GRAFT VERSUS HOST DISEASE (GVH)

It may be avoided by careful typing, It may be avoided by careful typing, removal of mature T cells from the graft removal of mature T cells from the graft and by immunosuppressive drugsand by immunosuppressive drugs

It is manifested by marked rise of several It is manifested by marked rise of several cytokines in patient’s serum (IFN-cytokines in patient’s serum (IFN-, TNF, , TNF, IL-1, IL-2, IL-4)IL-1, IL-2, IL-4)

RISK FACTORS IN FORMATION OF GVHRISK FACTORS IN FORMATION OF GVH

Acute GVHAcute GVHPrevious pregnancies in Previous pregnancies in female donorfemale donor

High T cell number in High T cell number in marrowmarrow

HLA disparityHLA disparity

Transplant from female to Transplant from female to malemale

Low immunosuppressionLow immunosuppression

Herpes virus infectionHerpes virus infection

Chronic GVHChronic GVHAging of donor and Aging of donor and recipientrecipient

Donor’s leukocyte Donor’s leukocyte transfusiontransfusion

Previous acute GVHPrevious acute GVH

High dosage radiationHigh dosage radiation

Transplant from female to Transplant from female to manman

HLA disparity HLA disparity

GRAFT VERSUS LEUKEMIA (GVL)GRAFT VERSUS LEUKEMIA (GVL)

It is reaction of donor’s lymphocytes from bone It is reaction of donor’s lymphocytes from bone marrow graft versus antigens on tumor cellsmarrow graft versus antigens on tumor cells

It is postulated that apart from GVH, there exists It is postulated that apart from GVH, there exists independent GVL componentindependent GVL component

GVL is due to T cells and NK cellsGVL is due to T cells and NK cells

Relapses of leukemia are rarer in those patients, Relapses of leukemia are rarer in those patients, who experienced GVH after marrow transplantwho experienced GVH after marrow transplant

GVL may be enhanced by transfusion of GVL may be enhanced by transfusion of lymphocytes obtained from marrow donors +IL-2lymphocytes obtained from marrow donors +IL-2

The fetus is allograft that is tolerated The fetus is allograft that is tolerated repeatedlyrepeatedly

Fetus carries paternal MHC and minor H antigens that Fetus carries paternal MHC and minor H antigens that differ from those of motherdiffer from those of motherStill, fetus is an allograft that is not rejectedStill, fetus is an allograft that is not rejectedWomen who born several children make antibodies Women who born several children make antibodies directed at father’s MHC proteinsdirected at father’s MHC proteins

Possible explanations of this puzzle:Possible explanations of this puzzle: Lack of classic MHC antigens on cells of trophoblast cells (TC) Lack of classic MHC antigens on cells of trophoblast cells (TC)

(protection from maternal T cells)(protection from maternal T cells) Presence of HLA-G antigens on TC (protection from NK cells)Presence of HLA-G antigens on TC (protection from NK cells) Secretion of suppresive cytokines by TC and uterine epithelium Secretion of suppresive cytokines by TC and uterine epithelium

(TGF-beta, IL-10, IL-4)(TGF-beta, IL-10, IL-4)

PERSPECTIVES OF XENOGENEIC PERSPECTIVES OF XENOGENEIC GRAFTSGRAFTS

Potential advantage due to larger Potential advantage due to larger accessibility of animal organsaccessibility of animal organs

Monkeys are apparently the most suitable Monkeys are apparently the most suitable donors, but dangerous because of donors, but dangerous because of potential risk of retrovirus transfer within potential risk of retrovirus transfer within graftgraft

PERSPECTIVES OF XENOGENEIC PERSPECTIVES OF XENOGENEIC GRAFTSGRAFTS - 2 - 2

Pigs are now considered because of Pigs are now considered because of similar sizes of organs and erythrocytes to similar sizes of organs and erythrocytes to human oneshuman ones

The major obstacle – presence in man The major obstacle – presence in man (1%) of natural antibodies vs.(1%) of natural antibodies vs. Gal Gal (galactose-(galactose--1,3-galactose) causing -1,3-galactose) causing hyperacute rejectionhyperacute rejection

Thank you for your attentionThank you for your attention

and perseveranceand perseverance!!