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 be rejected.
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. 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

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. 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

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

20. ?

21. 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:

22. 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.

23. 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.

24. 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.

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 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.

27. 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.

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 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.

30. 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.

31. 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.

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

33. 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.

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 IgM production of B Ly
week 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)