Prepared by : Ahlam Mousa Hadeel El- Jamal Seham Jaber Shatha Abo Ishaq

1. Immunological aspect of transplantation Prepared by : Ahlam Mousa Hadeel El- Jamal Seham Jaber Shatha Abo Ishaq Under supervision : Dr . Mansour Al yazji

2. Introduction • It is new treatment for patients of organ failure. • Initially performed between twins after that performed between non twins cases. • The main problem is graft rejection . • Immunosuppression still has the aim of “tolerance” , which in turn increase susceptibility to tumors and infections .

3. definitions • Autograft : transfer of an individuals own tissue to another site in the body. • Syngeneic or isograft : is transfer of tissue between genetically identical twins • Xenograft : is transfer of tissue between different species . • Allograft : is graft between genetically different members of the same species.

4. What's the factors that affect fate of transplantation • surgical technique . • degree of HLA matching between donor and recipient . • Types of organ that transplanted for example liver is more tolerogenic than others. • The ABO antigen system is also important in solid organ graft outcome but does not directly affect hematopoietic stem cell transplantation (HSCT).

5. Immunological consideration of transplantation • MHC comprises a set of genes on the short arm of chromosome 6. These genes are highly polymorphic and are codominantly expressed. • In general, class IMHC molecules present peptides to CD8+ T cells, while class II MHC molecules present peptides to CD4+ T cells ( MHC Restriction) . • this process can determine acceptance or rejection of the donor graft.

6. Contd,. • Every individual expresses three different pairs of class I molecules (designated as HLA-A, HLA-B, and HLA-C) and three different pairs of class II molecules (designated as HLA-DP, HLA-DQ, and HLA-DR). • Class I MHC molecules are expressed on all nucleated cells, whereas class II MHC molecules are expressed on antigen-presenting cells . • Matching the class I and class II MHC genes between the graft and recipient has varying degrees of Influence on graft–host interactions and tolerance, differing somewhat with the inherent immunogenicity or tolerogenicity of the organ being transplanted. • Histocompatibility between the donor and recipient is • primarily defined by genes of the MHC

7. Laboratory testing for compatibility in transplantation • Serologic evaluation • DNA-based HLA typing methods : • By using the polymerase chain reaction (PCR), polymorphic residues of both class I and class II HLA or MHC molecules can be amplified using primers that bind to the conserved regions of the gene.

8. ABO Blood Typing : • ABO antigens are primarily expressed by erythrocytes but also can be expressed by platelets and glandular epithelial and endothelial cells. • Incompatibility occurs when recipients lacking a certain blood type produce IgM antibodies against that antigen and cause subsequent activation of complement and lysis of transfused incompatible red blood cells.

9. Screening for Preformed Antibodies • Patients awaiting cadaveric organs undergo screening of their blood for preformed antibodies gainst HLA molecules.. Because transplantation across a positive cross match can cause hyperacute or acute rejection, patients with high PRAs typically experience longer waiting times on the cadaveric organ donor list.

10. Cross Matching In solid organ transplants, cross matching is usually done after a potential donor is identified. The recipient’s serum is tested for reactivity to the donor’s lymphocytes using the previously mentioned complement- mediated lysis or flow cytometric assays.

11. TYPES OF SOLID ORGANALLOGRAFT REJECTION • Hyperacute Rejection: Occur within minutes of engraftment and is due to reaction of performed anti- ABO antibodies in recepient with ABO antigens on the surface of endothelium of the graft . It is called white graft because the graft turn white as a result of the loss of the blood supply caused by spasm and occlusion of the vessels serving the graft .

12. Contd,. • Acute Rejection : Acute rejection is an inflammatory process affecting the vasculature and parenchyma of the allograft, which occurs a few days to a week after transplantation. Activated T cells can cause direct lysis of the graft or release cytokines that promote inflammation in the allograft.

13. Contd,. • Chronic Rejection : Fibrosis with intimal thickening and eventual occlusion of medium-sized arteries that supply the graft characterizes chronic rejection, occur months to year after engraftment .

14. Prevention and management of solid organ allograft rejection • Induction Agents Induction agents are immunosuppressive drugs given intraoperatively and immediately postoperatively to deplete the T-cell population.

15. Contd,. Examples for induction agents: • OKT3 is a murine monoclonal antibody to the CD3 complex of the T cell,an intrinsic part of the T-cell receptor. OKT3 also blocks the function of killer T cells . • Basiliximab (Simulect) and daclizumab (Zenapax) are humanized anti-CD25 monoclonal antibodies directed against the α chain of the high-affinity IL-2 receptor.

16. Contd,. • Alemtuzumab (Campath 1H) is an • anti-CD52 monoclonal antibody that is • gaining acceptance as an induction agent • for steroid-free protocols • Rituximab (Rituxan) is a monoclonal antibody against the CD20 antigen on B lymphocytes.

17. Maintenance immuniosuppressive drugs • Example • cyclosporine inhibit activation of NFAT (nuclear factor of activated T cells). This prevents IL-2 and other cytokine gene activation. Cyclosporine also promotes TGF-β activation, which may account for the fibrosis noted in allograft parenchyma with prolonged use of this drug.

18. Contd,. • Azathioprine (Imuran) is a purine analog that inhibits purine nucleotide synthesis and interferes with RNA synthesis . • Corticosteroids have been mainstay drugs for transplantation

19. Contd,. • Standard maintenance immunosuppression consists of at least two or three drugs.. • . Steroid free protocols are gaining popularity in solid organ allografts to avert the long-term side effects of steroid use

20. Solid organ transplantation outcomes • The half-life of kidney transplants has been increasing and is currently more than tenyears. Failures are mainly due to chronicrejection, nephrotoxicity of the calcineurin inhibitor agents, and recurrent disease. • For liver the problem for transplantation is hepatitis c which cause graft loss. • For heart, the problem is related to chronic graft rejection and atherosclerosis

21. Hematopoietic stem cell transplantation • HSCT involves the infusion of immature blood-forming cells into the circulation of a patient to reconstitute the recipient’s bone marrow. • HSCT is a promising form of therapy for patients with certain forms of genetic diseases, specific cancers, and various blood disorders. • The transplanted hematopoietic stem cell (HSCs) may com from patient autologous HSCT ,or from different stem cell donor “allogeneic HSCT”

22. Graft versus host disease • During GvHD, the engrafted,immunocompetent donor cells recognize the host as foreign and mount an immunologic attack. • The dominant immunologic factors underlying GvHD are the HLA compatibility between donor and recipient and the presence of immunocompetent T cells in the graft.

23. Contd,. • There are two forms of GvHD : • Acute GvHD is primarily T-cell and cytokine mediated • chronic GvHD is thought to be B-cell and antibody mediated .

24. Clinically:- • Clinical manifestations of acute GvHD can run the gamut from mild skin rash, anorexia, mild diarrhea, or low-grade cholestasis to full thickness skin sloughing, liters of bloody diarrhea, and severe liver dysfunctionwith lethal consequences. • Chronic GvHD resembles autoimmune diseases, for example,scleroderma, in many of its manifestations.

25. Treatment • Treatment of GvHD, however,can involve increasing layers of immune suppression, which can result in serious morbidity or even death.

26. Important Developments inSupportive Care • First is the increasingly sensitive and early detection of opportunistic infections like cytomegalovirus, among others. • Equally important are the increasingly effective pharmaceuticals for prophylaxis, preemptive therapy, and actual treatment.