TRANSPLANTATION IMMUNOLOGY

1. TRANSPLANTATION IMMUNOLOGY 2018. 05. 17.

2. Transplantation Replacement of non-functioning organ/tissue with a healthy one, taking cells, tissues, or organs, called a graft, from one individual (donor)and placing them into a (usually) different individual(recipient, host) orthotopic transplantation: the graft is placed into its normal anatomic location, heterotopic transplantation: the graft is placed in a different site, • Transplantationantigens: • Histocompatibilityantigens • Histo-incompatibilityrejection • Products of the main histocompatibilitycomplex: • MHCI, MHCII : co-dominant mendelien inheritance • HLA human (HumanLeukocyteAntigen), mice: H2 • Minor histocompatibilityantigens (minor-Hantigens) • Bloodgroupantigens • A, B, AB, O

3. People in the United States living with functioning organ grafts, 1999-2007

4. Graft rejection is the result of an adaptive immune response Lymphocytes from B mice rejected the graft Peter Medawar, Nobel price 1960

5. The genetics of graft rejection

6. Recognition of transplanted cells as self or foreign is determined by polymorphic genes, called histocompatibility genes, which differ among different members of a species. • The basic rules of transplantation immunology: • Graft from genetically identical indiviuals,(identical twins or members of the same inbred strain of animals) are never rejected. • Cells or organs transplanted between genetically nonidentical people or members of two different inbred strains of a species are almost always rejected. The offspring of a mating between two different inbred strains of animal will typically not reject grafts from either parent. In other words, an (A × B)F1 animal will not reject grafts from an A or B strain animal. • A graft derived from the offspring of a mating between two different inbred strains will almost always be rejected by either parent. In other words, a graft from an (A × B)F1 animal will be rejected by either an A or a B strain animal.

7. Such results suggested that the molecules in the grafts that are responsible for eliciting rejection must be polymorphic and their expression is codominant. Polymorphic refers to the fact that these graft antigens differ among the individuals of a species (other than identical twins) or between different inbred strains of animals. Codominant expression means that every individual inherits genes encoding these molecules from both parents and both parental alleles are expressed.Therefore, (A × B)F1 animals express both A and B alleles and see both A and B tissues as self, whereas inbred A or B animals express only one allele and see (A × B)F1 tissues as partly foreign. This is why an (A × B)F1 animal does not reject either A or B strain grafts and why both A and B strain recipients reject an (A × B)F1 graft.

8. Combinatons of MHC allotypesinindividuals and population locus allels haplotype genotype Genetical polymorphism of the population allels haplotype Indiviual 1. Indiviual 2. Most of the antigens that stimulate adaptive immune responses against allografts are proteins encoded by polymorphic genes that differ among individuals.

9. Direct and indirect alloantigen recognition -1.

10. Direct and indirect alloantogen recognition - 2

11. Activation of alloreactive Tcells

12. Molecular basis of direct recognition of allogeneic MHC molecules. Direct recognition of allogeneic MHC molecules may be thought of as a cross-reaction in which a T cell specific for a self MHC molecule-foreign peptide complex (A) also recognizes an allogeneic MHC molecule (B, C). Nonpolymorphic donor peptides, labeled "self peptide," may not contribute to allorecognition (B) or they may (C).

13. Influence of MHC matching on graft survival

14. The mixed lymphocyte reaction (MLR). In a one-way primary MLR, stimulator cells (from donor Y) activate and cause the expansion of two types of responder T cells (from donor X). CD4+ T cells from donor X react to donor Y class II molecules, and CD8+ T lymphocytes from donor X react to donor Y class I MHC molecules. The CD4+ T cells differentiate into cytokine-secreting helper T cells, and the CD8+ T cells differentiate into CTLs. APC, antigen-presenting cell.

15. Immune mechanisms of graft rejection. A, In hyperacute rejection, preformed antibodies reactive with vascular endothelium activate complement and trigger rapid intravascular thrombosis and necrosis of the vessel wall. B, In acute rejection, CD8+ T lymphocytes reactive with alloantigens on endothelial cells and parenchymal cells mediate damage to these cell types. Alloreactive antibodies formed after engraftment may also contribute to vascular injury. C, In chronic rejection with graft arteriosclerosis, injury to the vessel wall leads to intimal smooth muscle cell proliferation and luminal occlusion. This lesion may be caused by a chronic DTH reaction to alloantigens in the vessel wall.

16. Histopathology of different forms of graft rejection. A, Hyperacute rejection of a kidney allograft with endothelial damage, platelet and thrombin thrombi, and early neutrophil infiltration in a glomerulus. B, Acute rejection of a kidney with inflammatory cells in the connective tissue around the tubules and between epithelial cells of the tubules. C, Acute antibody-mediated rejection of a kidney allograft with destructive inflammatory reaction destroying the endothelial layer of an artery. D, Complement C4d deposition in vessels in acute antibody-mediated rejection. E, Chronic rejection in a kidney allograft with graft arteriosclerosis. The vascular lumen is replaced by an accumulation of smooth muscle cells and connective tissue in the vessel intima.

17. PREVENTION AND TREATMENT OF ALLOGRAFT REJECTION

20. ABO Blood Group Antigens A, Blood group antigens are carbohydrate structures added onto cell surface proteins by the action of glycosyltransferases. Most people inherit a gene that encodes l-fucosyltransferase, which produces the H antigen. Inheritance of a gene for N-acetyl-d-galactosaminyl transferase, which generates the A antigen, and the gene that encodes d-galactosyltransferase, which generates the B antigen, varies between people. A person who does not inherit genes for either of these enzymes will be type O; a person who inherits only one of these glycosal transferase genes will be type A or B; and a person who inherits genes for both enzymes will be type AB.

21. Therapeutical possibilities using regulatory cells Sakaguchi S, 2005 NI 6:345 Karim M; 2002, Curr Op Immun, 14:584

22. Wood KJ; 2003, NRI 3:199

23. Bone marrow trasplantation • Diseases with genetical origin (primary immunodefficiencies, enzyme defficiencies) • tumorterapy • Inducing tolerance upon transplantation: • All MHC loci • Irradiated recipient Stem cell: self-renewing, able to give rise to different types of cells Multipotent stem cells Progenitor cells – limited self renewing, fast proliferating cells Hemopoetic stem cells: sources: BM, blood, umbilical cord blood, foetal liver, BM, liver, yolk sac General characteristics: Self renewing proliferation differentiation – aktivation - apoptosis

24. Re-appearance of T cells after BMT Moss P; 2005, NRI 5:9

25. T cell populations after BMT Brink van den MRM; 2004, NRI 4:856

26. Xenotransplantation • advantage : unlimited availability • disadvantges:: presence of hyperacut antibodies, virus etc.causing hyperacut rejection • preferred species: pig • Therapeutical possibilities: Cascalho M; 2001, NRI 1:154

27. Embrio as allograft Trophoblasts: HLA-G, HLA-E expression  limited polymorphism, no allodeterminants No Tc and NK activity – sHLA-G inhibitory effect Vδ1 TCR (decidua) - TH2, TH2 shift, Treg cells, decidual NK cells Progesteron induced blocking factor

28. NK T g/d B EMBRIONIC SIDE MOTHER SIDE HLA-G TROPHOBLAST HLA-E RECOGNITION, EFFECTOR MECHANISMS ANTIGENPRESENTATION

29. Mechanism of theimmunesuppression EMBRIONICANTIGEN PRESENTATION (TROPHOBLAST) PROGESTERONE RECEPTOR g/dOR CD8+ CELLS B PROGESTERONE TH1/TH2 BALANCE PIBF Th LOW NK ACTIVITY BLOCKING ANTIBODIES