Immunological aspects of transplantation and pregnancy

1. Immunological aspects of transplantation and pregnancy

2. Immunologically „non-self” cells/tissues Tumors Transplanted tissues Embryo

3. Brief history of transplants • 1933: First human-to-human kidney transplant (kidney never functioned). • 1954: First successful kidney transplant from one twin to another with no anti-rejection drugs necessary. • 1967: First successful liver transplant. • 1967: World's first heart transplant. • 1978: Uniform Brain Death Act passed - "Brain death" IS death. • 1983: Cyclosporine, a revolutionary anti-rejection drug, approved for commercial use, sparking a huge increase in transplants.

4. Transplantation • Self • Non-self • Transplantation - immunological tolerance to non-self (cell, tissue, organ) • Main factors: • T and B lymphocytes • genetic polymorphism of MHC glycoproteins

5. Types of Transplantation • natural - pregnancy • arteficial - therapic transplantation (including transfusion of blood !) • ortotopic - the graft transplanted to identical locus • heterotopic - transplantation to non- identical parts of the body

6. Types of Transplantation • Autograft: Transplant from one area to another on the same individual - no immune response. • Isograft/Syngraft: Transplant from one individual to another genetically identical – no immune response. • Xenograft: Transplant from donor to a recipient of a differet species - immune response, the transplant may berejected. • Allograft: Transplant from one individual to a genetically dissimilar(allogenic) individual of the same species - immune respons, rejection (the most common)

7. Significant Transplantation Antigens • MHCs - Mendelian, codominant inh. • MHC I. - expressed on each nuclear cell - infection with viruses or tumors can result the total loss of MHC I. • MHC II. - expressed on APC-s - cytokines or inflammation can induce their expression on other cells • Minor MHC-s

8. Human Leukocyte Antigen - HLA • Coded on Chr. 6p • Polymorphism: DRb B DPb A C DQb DQa DPa DRa MHC I. MHC II.

9. Minor-H Antigens • Any polymorph peptide presented on the graft • They are bound to MHC I. • They can not induce synthesis of antibodies BUT • They are recognized by Tc lymphocytes • Their diversity can enhance the intensity of immune reactions in the case of MHC divergence • They can induce rejection also in the case of total MHC identity

10. enzyme Blood-Groups • Alloantigens of RBCs • AB0 - coded on the Chr.9 • a glycosphingolipid is coded by the dominant H-gene (this is independent from the AB0 !) • enzymes - expressed differently in A or B allels - are responsible for differences • these enzymes can modify with an N-acethyl-galactiseamine or galactose the lipid The antigens are present on bacteria of intestine, therefore immunity develops towards the non-self antigens, while the selfs are tolerated

11. Rh-antigens • Responsible genes are on Chr. 1 • Antigens: D, d, C, c, E, e • The antigens are expressed ONLY on RBCs • Immuneresponse (IgG) is a result of alloimmunizations - e.g. transfusion or pregnancy

12. 1st pregnancy Rh-incompatibility Rh- cell (mother) Rh+ cell Rh specific B cell memory B cell (in mother) 2nd pregnancy memory B cell plasma cell + anti Rh IgG

13. Recognition of alloantigens • Th Ly cells - release of cytokines • Tc Ly cells - effector functions, inflammation • NK Ly cells - “ “

14. Alloantigen-presentation Direct presentation Indirect presentation Recipient T Ly Recipient T Ly Donor APS Recipient APS Donor MHC + donor/recipient peptide Recipient MHC + donor peptide

15. Criteria of Donor-selection • Main criteria - the identity of HLA antigens • Living persons - time is given for identification of all HLA markers • Identical twins > sisters or brothers (25% identity of haplotypes) > parents > other relative • Cadaver - the time is limited; AB0, RhD, HLA-A, -B, -DR are tested • More criteria: to belong the same population; to find a genetically close donor - network of transpl. centr.

16. Xenogene transplantation • interspecies transplantation • apes and swine - kidney, heart BUT • hyperacute rejections - IgM -Gala1-3Gal • NK Ly and monocytes attracted by endothel • expr. of adhesion molecules induced by chemokines MORE problem: the interspecies transfer of retroviruses

17. Pretreatment of recipient and the graft • Prior immunization of the recipient ? • Exemption of graft from T Ly and APC-s (perfusion of vascular syst of the graft -heart or kidney- removes the passanger leukocytes; UV irradiation - inhibits APCs) • Immunosuppressive therapy - before and after TP Problem: these patients are highly sensible to pathogens and tumors

18. Transplantation of Bone-marrow • hemopoetic stem cells are introduced into the peripherial blood • high ratio of adhered cells - high number of colonies - differentiation • the age of recipient and donor is significant • some cells of adult are not repleaced by TP e.g. gd TCR or B1 Ly are available from umbilical cord or embryonic liver • results a chimera: APCs - recipient T Ly - donor

19. Graft versus Host reaction (GVH) • special problem of bone-marrow transplantation • intensity depends on the number of T Ly • skin, liver, stomach and intestine are affected • acute GVH: chr. inflammation - Th1 activation, IFNg and TNF • chronic GVH: Th2, autoimmune Prevention: removal of mature T Ly from the bone-marrow, BUT this might decrease the ability of adherence

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21. Transplant Rejection • The immune system recogizes the transplantas foreign and respondsagainst it. • Rejection of transplanted tissue is mediated by T cells. • Rejection occurs in xenografts and allografts. • There are three clinical characteristics of allograft rejection:

22. Hyperacute rejection: • Destruction of transplant by preformed antibodiessynthesized as a result of previous transplantation. • This type of rejectionoccurs within a few minutes or hours of transplantation.

23. Chronic rejection: • Transplant destruction caused by cell mediated immunityand antibodies. • This type of rejection occurs months after transplant hasassumed normal function and may result in a complete failure of transplant.

24. Acute rejection: • Destruction of transplant caused by cell-mediated immunityin recipients not previously sensitized to transplant. • This type of rejectionbegins a few days after transplantation and may result in a complete loss oftransplant function. • It is manifested by infiltration of lymphocytes and macrophages at the rejection site. • Acute rejetion may be reduced byimmuosuppresive therapy.

25. Factors determining the rate of rejection • Type of transplanted tissue • The site of transplantation • Recipient's circulation • Lymphatic drainage • Expression of stong antigen on graft

26. MHC and rejection • MHC I antigens are targets for recipient CD8+ T cells inrejection. • Donor MHC II molecules are present on specialized cells in atransplant. • MHC II antigens are targets for recipient CD4+ T cells inrejection. • MHC II molecules are most effective at generating an immuneresponse.

27. Prolongation of Transplants= Clinical Immunosuppression • Involves a non-specific suppression of bothcell-mediated and humoral immunity. • Focuses on lymphocytic interaction andproliferation, and lymphocytedepletion.

28. . Antiproliferative agents:antimetabolites, alkylating agents,cyclosporine, FK506, antibiotics Lymphocyte depletion agents: cytotoxic, blocking agents,anti-inflammatory agents

29. Cyclosporine • the most common immunosuppressive drug • a cyclicmetabolic peptide • inhibits Tcell-receptor-mediated activation events • interferes withcytokine gene transcriptionin T cells • suppressing the production ofinterleukins, IL-1, IL-2,IL-3, IL-4 and IFN-gamma. • the most effective administered prior to transplantation. • Problems:nephrotoxicity, hypertension, B cell lymphoma, increased hair growth on the face • and body.

30. Cytotoxic and Blocking Agents • Antilyphocyte serum (ALS) or antilymphocyte globulins(ALG), and monoclonal antibodies such as OKT3. • ALS or ALG is producedwhen lymphocytes are injected into animals of different species (rabbit, horse) Directedspecifically against lymphocytes. • OKT3 is a monoclonal antibody to CD3 ofthe TcR. These block recognition of MHC I and II antigens on atransplant.

31. Anti-inflammatory Agents • Common anti-inflammatory agents include corticosteroids, (prednisone,prednisolone, and methyl prednisolone). • These anti-inflammatory agentsinhibit cytokine synthesis of IL-2, IL-6, and INF-gamma. • They prevent therelease of harmful lysosomal enzymes and induce lysis of lymphocytes. • They also reduce phagocytosis and killing by neutrophilsand macrophages, as well as MHC II expression.

32. Effects of Immunosuppressive Therapy Cancer: • Nonmelanotic skinand lip cancer (39%) • Lyphoproliferativedisorders (LPD) (14%) • Cervical cancer (8.6%)

33. Infection • Risk is influenced by the type of trasplant, exposure to potentialpathogens, dose, duration and temporal sequence of immunosuppressivetherapy. • Infection accounts for 40% of all deaths among transplant patients.

34. Pregnancy The embryo is considered as an allograft which is tolerated by the maternal immune system - even in consecutive pregnancies.

35. Immunological backgrounds of tolerance in pregnancy • trophoblast cell do not express MHC I and II. or costimulatory molecules • trophoblast are not targets of Tc Ly and not APCs of Th Ly • HLA-G gene codes an MHC I.-like protein: they can mask the placenta to T Ly and inhibit NK Ly by their MHC character • trophoblast leukocyte crossreactive antigen (TLX) inhibits C3b deposition on trophoblast

36. Immunosuppressive hormones of pregnancy • progesterone, estrogen • corticosteroids • AFP

37. week 6 - complement proteins - thymus • week 11 - IgM production of B Ly • week 12-13 - mitogen response - GVH reactions BUTthe immunity is provided by the maternal IgG (after birth colostrum provides IgA, phagocytes, lymphocytes and bactericide enzymes for 6 months)