Immunological basis of graft rejection and mechanism of graft rejection

It contains, what is transplantation and their types and also include the mechanism graft rejections. the treatment of graft rejection.

1. Immunological basis of graft rejection and mechanism of graft rejection F athima Hameed

2. Outlines Transplantation History Types of graft Graft acceptance Graft rejection Mechanism of allograft rejection Graft versus host reaction Immunosuppression reference

3. Transplantation Transplantation is the process of moving cells, tissues, organs from one set to another, either within the same person or between a donor and a recipient. The immune system plays a critical role in transplantation. The complex mechanisms of immunity, which under normal circumstances work to identify foreign microbes and direct the immune system to destroy them.

4. History of transplantation Sir peter Medawar- ‘father of transplantation’. He works on graft rejection and acquired immune tolerance in 1944 showed that skin allograft between two mice are rejected. Alexis carrel ( france ) work on vascular structure and the transplantation of blood vessels and organ. In 1954, the first successful human kidney transplant was performed between twins in boston . Schwartz and Dameshek , in 1959, showed that 6-mercaptopurine was immunosuppressive in rats, ushering in the era of immunosuppressive drug treatment. The 1 st successful liver transplant by Dr. Thomas E. starlz in 1967 the 1 st heart transplantation by Christian barnard in 1967 the 1 st successful bone marrow transplant by E. Donnall Thomas in 1968 .

5. Types of graft

6. Graft acceptance Immune system do not stimulate the immune response against all the antigens present in the graft, and no graft rejection even when the donor and recipient are not syngeneic. This is called as graft acceptance.

7. Graft rejection The intensity of the immune response against the organ or tissue, also commonly referred to as the “ grafts rejectionˮ . Rejection is a complex process in which “recipient immune system recognize the graft as foreign and attacks itˮ . It involves; 1.Cellular mediated rejection 2.antibody mediated rejection

8. Cellular mediated rejection These rejection is mediated by lymphocytes that have been activated against donor antigens, primarily in the lymphoid tissues of the recipient. The donor dendritic cells enter the circulation and function as antigen presenting cells (APCs). Destruction of grafts occur by CD8+CTLs and CD4+helper cells. 2 type of pathways are involved; 1. Direct pathway 2. Indirect pathway

9. Cellular mediated rejection

10. Celular mediated rejection Direct pathway: Acute graft rejection Recognition of self vs. non-self - T cells recognize alloantigens - T cells stimulated by APCs from donor. T cell activation and proliferation Indirect pathway: T cell recognize foreign antigens from donor Recipient APCs present these antigens Also lead to T cell proliferation

11. Antibody mediated rejection Antibody mediated rejetion (AMR) defines all allograft rejection caused by antibodies directed against donor – specific HLA molecules, blood group antigen (ABO)- isoagglutinins , or endothelial cell antigens. It is also called as humoral rejections. It have 3 types, 1.Hyperacute rejection 2.Acute rejection 3. Chronic rejection

12. Antibody mediated rejection Hyper acute: It is caused by the presence of preexisting antibodies of the recipient, that match the foreign antigens of the donor, triggering an immune response against the transplant. Acute: Acute rejection will occur in all transplantations, except between identical twins. Acute rejection is caused by the formation of antibodies following the detection of non-self antigens in the donated graft. Chronic: Repeated episodes of acute rejection can ultimately lead to chronic rejection of the graft and failure of the transplant.

13. Time course of graft rejection Hyper acute – within 1 st 24 hours Acute rejection – within 1 st few weeks Chronic rejection – months to years

14. Allograft rejection The 1 st set response: When skin from rabbit is applied to another genetically unrelated animal- Initially the graft is accepted. Vascularization starts. Remains healthy for 2-3 days. By 4 th day, inflammation starts, lymphocytes & macrophages invade. BVs occluded by thrombi , vascularity diminishes, ischemic necrosis sets in. graft changes to scab-> sloughed off by 10 th day. This is called “1 st set response”.

15. Allograft rejection The 2 nd set response: If, in an animal, which has rejected a graft by 1 st set response, another graft from the same donor is applied- The graft is rejected in an accelerated manner. Vascularization is attempted but is soon interupted by innflammatory response. Necrosis sets in early, graft is sloughed off by 6 th day. This accelarated allograft rejection is called “2 nd set response.”

16. Allograft rejection

17. Mechanism of allograft rejection Basic immunological: Clear from specificity of second set response. Accelerated rejection is seen only if the second graft is from the same donor as the first. Application of a skin graft from another donor will evoke only the first set response. Allograft accepted if the recipient animal is made immunologically tolerant: If spleenic cells of the donor are rejected into recipient fatal / neonatal animal, they will accept the graft at a later time. This is due to specific immunological tolerance.

18. Mechanism of allograft rejection Transplantation immunity is predominantly cell mediated: 1 st set response almost exclusively by t cells. Humoral Ab’s are also produced. They have soome role in 2 nd set response. Hyperacute rejection: If transplantation is attempted in animals having high titre of Ab against graft Ag’s, the graft remains pale & is rejected in matter of hours. This is also called as “white graft response.” Seen in human kidney transplantation when there is high Ab titre due to previous transplantation, blood transfusion / pregnancies.

19. Immunological enhancement Humoral antibodies may sometimes act in opposition to cell mediated immunity, by inhibiting graft rejection. This phenomenon, called “immunological enhancementˮ was originally described by kaliss in tumor transplants.

20. Mechanism of enhancing effects Ab may combine with the Ag released from the graft, thus inhibiting initiation of immune response (Afferent inhibition) Ab may combine with the lymphoid cells of appropriate specificity and, by negative feedback mechanism stop response (Central inhibition). Surface of graft cells may be coated by Ab thus preventing sentisized lymphocytes coming in contact with them (Efferent ) Allograft immunity is a generalized response directed against all the antigens of the donor. A recipient sensitized by a skin graft will reject by the second set response not only another skin graft but also any other organ or tissue graft from the same donor.

21. Graft versus host reaction In some instance the graft tissue elicits an immune response against host Ag & that immune response is called graft vs. host reaction Graft vs. host reaction brings damage to the host cell & host When grafted tissue has mature T cells, they will attack host tissue leading to GVHR.

22. Mechanism of GVHR Graft lymphocytes aggregate in the host lymphoid organ. Graft lymphocytes are stimulated by the host lymphocytes. Stimulated lymphocytes of graft produce lymphokines Lymphokines activate host T-cell which produce polyclonal B-cell activation Activated B-cell react with the self Ag’s & cause damage to the host cell

23. Immunosuppression To reduce the risk of transplant rejection, patients are treated with immunosuppressive drugs that will dampen their immune response. These drugs are; Azathioprine Steroids Rapamycin Cyclosporine Monoclonal antibodies. Immunosuppressive drugs are given in two phases; 1.an initial induction phase involving a high dose 2.a later maintenance phase which involves using the drug in the long term at a lower dose. Immunosuppression drugs are associated with adverse side effects, high blood pressure impaired renal function diabetes mellitus increased risk of cancer.

24. References Text book of microbiology – Ananthanarayan & Paniker’s , 9 th edition. www.immunology.org/policy-and-public-affairs/briefings-and-positions-statements/transplant-immunology https://www.slideshare.net/mobile/ARYAGEORGE1/graft-rejection https://www.slideshare.net/mobile/svasan3/transplant-rejection www.quora.com/what-are-the-types-of-graft-and-their-resources https://www.slideserve.com/kurene/immunology-of-transplantation-malignancy

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