Immunological aspects of transplantation and pregnancy

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

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.

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

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

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 be rejected. Allograft: Transplant from one individual to a genetically dissimilar (allogenic) individual of the same species - immune respons, rejection (the most common)

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

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

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

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 enzyme

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

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

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

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

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.

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

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

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

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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Transplant Rejection The immune system recogizes the transplant as foreign and responds against it. Rejection of transplanted tissue is mediated by T cells. Rejection occurs in xenografts and allografts. There are three clinical characteristics of allograft rejection:

Hyperacute rejection: Destruction of transplant by preformed antibodies synthesized as a result of previous transplantation. This type of rejection occurs within a few minutes or hours of transplantation.

Chronic rejection: Transplant destruction caused by cell mediated immunity and antibodies. This type of rejection occurs months after transplant has assumed normal function and may result in a complete failure of transplant.

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

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

MHC and rejection MHC I antigens are targets for recipient CD8+ T cells in rejection. Donor MHC II molecules are present on specialized cells in a transplant. MHC II antigens are targets for recipient CD4+ T cells in rejection. MHC II molecules are most effective at generating an immune response.

Prolongation of Transplants = Clinical Immunosuppression Involves a non-specific suppression of both cell-mediated and humoral immunity. Focuses on lymphocytic interaction and proliferation, and lymphocyte depletion.

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

Cyclosporine the most common immunosuppressive drug a cyclic metabolic peptide inhibits T cell-receptor-mediated activation events interferes with cytokine gene transcription in T cells suppressing the production of interleukins, 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.

Cytotoxic and Blocking Agents Antilyphocyte serum (ALS) or antilymphocyte globulins (ALG), and monoclonal antibodies such as OKT3. ALS or ALG is produced when lymphocytes are injected into animals of different species (rabbit, horse) Directed specifically against lymphocytes. OKT3 is a monoclonal antibody to CD3 of the TcR. These block recognition of MHC I and II antigens on a transplant.

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

Effects of Immunosuppressive Therapy Cancer:   Nonmelanotic skin and lip cancer (39%) Lyphoproliferative disorders (LPD) (14%) Cervical cancer (8.6%)

Infection Risk is influenced by the type of trasplant, exposure to potential pathogens, dose, duration and temporal sequence of immunosuppressive therapy. Infection accounts for 40% of all deaths among transplant patients.

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

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

Immunosuppressive hormones of pregnancy progesterone, estrogen corticosteroids AFP

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