Immunology of Transplantation of cell, tissue and organ ppt.pptx

Transplantation- definition, important terms, types of grafts, Graft rejection, histocompatibility, ABO blood group compatibility, HLA typing, role of immune system, stages of graft rejection, types of rejection, general immunosuppressive therapy methods, specific immunosuppressive therapy, immune tolerance to allografts, clinical transplantation, database of transplantation history, kidney transplantation, bone marrow transplantation, heart transplatation, lung transplantation, liver transplantation, pancreas transplantation, skin transplantation, xenotransplantation

1. Immunology of organ and tissue transplantation

2. Introduction Transplantation is the act of transferring cells, tissues, or organs from one site to another. Graft: Implanted cell, tissue or organ
Donor: Individual who provides the graft
Recipient or host: Individual who receives the graft

3. Transplantation Immunity 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, pose a significant barrier to successful transplantation. Rejection of a transplant occurs in instances where the immune system identifies the transplant as foreign, triggering a response that will ultimately destroy the transplanted organ or tissue. To reduce the possibility of rejection, the donor and recipient are carefully matched for immune compatibility prior to transplantation.

4. The time sequence of allograft rejection varies according to tissue involved. Graft rejection always displays the attributes of specificity and memory.

5. Role of cell-Mediated responses Lymphocytes, but not serum antibody, could transfer allograft immunity (1950s by Avrion Menison ) T-cells derived from an allograft-primed mouse were shown to transfer second-set allograft rejection to an unprimed sygeneic recipient, as long as that recipient was grafed with the same allogeneic tissue. Analysis of the T-cell subpopulations involved in allograft rejection has implicated both CD4+ and CD8+ populations.

6. Both CD4+ and CD8+ T-cells participated in rejection and that the collaboration of both subpopulation resulted in more pronounced graft rejection.

7. HLA Typing Human Leukocyte Antigen typing HLA Typing Methods for Transplantation: Microcytotoxicity Test: Assessing MHC alleles via antibody-mediated cytotoxicity. Mixed-Lymphocyte Reaction (MLR): Quantifying class II MHC compatibility.

8. Advantages of Microcytotoxicity Test: Rapid results within a few hours.
Indicates presence or absence of MHC alleles.
Useful when immediate transplantation is necessary. Advantages of MLR: Better indication of T-cell activation.
Quantifies degree of class II MHC compatibility.
Provides insight into prognosis for graft survival.

9. Disadvantages of MLR: Takes several days to run the assay.
Not suitable for immediate transplantation needs, such as cadaver donors. Importance of MHC Matching: Kidney transplant survival primarily depends on donor-recipient matching of HLA class II antigens.
Data from kidney transplants show higher survival rates with class I mismatches compared to class II mismatches.

10. HLA matching is most important for Kidney and bone marrow transplants; liver and heart transplants may survive with greater mismatching. Role of Killer Inhibitory Receptors (KIR): NK cell recognition of class I antigens influences tissue acceptance (It’s absence May lead to graft rejection).
Rejection observed in bone marrow transplants because of absence of class I antigen Minor histocompatibility differences can also lead to graft rejection.

11. Successful transplantation requires consideration of both major and minor histocompatibility differences.
Immune suppression may be necessary even in HLA-identical transplants.

12. Sensitization stage CD4 & CD8 T-cells recognize alloantigens expressed on cells of the foreign graft & proliferate in response. Both major (MHC nd associated peptide linkage) and minor (response is weak) histocompatibility alloantigens can be recognized
Both dendritic cells & vascular endothelial cells from an allogeneic graft induce host T-cell proliferation.
The degree & type of immunologic response varies with the type of transplant.

13. Effector stage A variety of effector mechanisms participate, these are cell-mediated reactions involving delayed-type hypersensitivity & CTL-mediated cytotoxicity (most common). Less common mechanisms are-Ab plus-complement lysis and Destruction by ADCC. Recognition of foreign class I alloantigens by host CD8+ cells can lead to CTL mediated killing. Involves influx of T-cells & macrophages into the graft. (IFN-𝜸:DTH response ) Cytokines secreted by TH cells play a central role.

14. Immunosuppressive Therapy Necessary for allogeneic transplantation survival Disadvantages include nonspecific immunosuppression and increased infection risk Complications: increased cancer risk, hypertension, metabolic bone disease Mitotic inhibitors 3. Fungal metabolite Corticosteroids 4. Total lymphoid irradiation

15. 1.Mitotic Inhibitors Azathioprine (Imuran): blocks purine synthesis, diminishes B-cell and T-cell proliferation
Cyclophosphamide: alkylating agent disrupting DNA chain
Methotrexate: folic-acid antagonist, blocks purine biosynthesis 2. Corticosteroids Prednisone, dexamethasone: potent anti-inflammatory agents
Given with mitotic inhibitors to prevent acute graft rejection

16. 3. Fungal Metabolite Immunosuppressants Cyclosporin A ( CsA ), FK506 ( tacrolimus ), rapamycin ( sirolimus ) Block T cell activation and cytokine expression CsA : kidney, liver, heart, and heart-lung transplants, notable nephrotoxicity FK506, rapamycin : more potent, fewer side effects

17. 4. Total Lymphoid Irradiation TLI eliminates lymphocytes before transplant. X-ray targets: thymus, spleen, lymph nodes. Protocol: Daily 200 rads per day for weeks. Total 3400 rads Bone marrow spared for lymphoid stem cell renewal. Enhances graft acceptance by increasing tolerance. Timing critical for successful transplantation.

18. Specific Immunosuppressive Therapy Current immunosuppressive treatments lack specificity.
Goal: Develop antigen-specific immunosuppressants . 1.Monoclonal Antibodie Suppress graft rejection responses Monoclonal Antibodies ( mAbs ) for T-Cell Suppression Target various surface molecules on immune cells. Can suppress T-cell activity or target activated T cells. Strategies: Depletion of specific cell populations or blocking co-stimulatory signals.

19. CD3 Monoclonal Antibody Therapy Depletes mature T cells from circulation.
Induces rapid depletion via binding to Fc receptors on phagocytic cells. High-Affinity IL-2 Receptor (anti-TAC) Therapy Blocks proliferation of activated T cells responding to graft antigens.
Specific for activated T cells expressing high-affinity IL-2 receptor.

20. Nondepleting Antibody Therapy Example: Anti-CD4 antibodies induce T cells into an immunosuppressed state without reducing CD4+ T-cell count. Adhesion Molecule Targeting Simultaneous targeting of adhesion molecules ICAM-1 and LFA-1 permits indefinite survival of cardiac grafts.

21. Challenges and Solutions Limitation: Mouse-origin mAbs can induce recipient antibody response.
Solution: Human monoclonal antibodies and mouse-human chimeric antibodies. Cytokine-Specific Antibody Therapy Targets cytokines implicated in allograft rejection (TNF-, IFN--, IL-2).
Prolongs graft survival and reduces graft-versus-host disease in animal bodies

22. 2. Blocking Co-stimulatory signals induce Anergy T-cell activation requires co-stimulatory signals in addition to T-cell receptor signaling .
Interaction between B7 molecule on antigen-presenting cells and CD28/CTLA-4 on T cells provides co-stimulation. Co-Stimulatory Molecules: CD28: Expressed on both resting and activated T cells; binds B7 with moderate affinity.
CTLA-4: Expressed at lower levels, only on activated T cells; binds B7 with 20-fold higher affinity.

23. CD40 and CD40 ligand (CD40L/CD154) are another pair of co-stimulatory molecules required for T-cell activation. Experimental Evidence: Lenschow , Bluestone, and colleagues demonstrated blocking B7-mediated co-stimulation with CTLA-4 after transplantation induced T-cell anergy .
Used CTLA-4Ig, a soluble fusion protein, to block co-stimulation.
Resulted in long-term survival of xenogeneic grafts in mice.

24. Extension to Clinical Trials: Allan Kirk, David Harlan, and colleagues extended findings to kidney transplantation in monkeys.
Treated recipients with CTLA4-Ig or anti-CD40L monoclonal antibody, or both.
Animals given both reagents showed no rejection at 150 days post-transplantation.
Clinical trials planned for humans, aiming to revolutionize transplantation procedures.

25. Immune Tolerance to Allografts Immune tolerance to allografts refers to instances where graft acceptance occurs without immunosuppressive measures.
Two main scenarios: privileged sites and induced biological tolerance.

26. Privileged Sites Certain anatomical locations lack lymphatic and sometimes blood vessels, preventing immune surveillance.
Examples include the anterior chamber of the eye, cornea, uterus, testes, and brain.
The blood-brain barrier and absence of lymphatics contribute to immunological privilege.
Successful examples: corneal transplants, islet cell transplantation into the thymus in diabetes models.

27. Physical Sequestration Experimentally, graft cells can be physically sequestered using semipermeable membranes.
Example: encapsulation of pancreatic islet cells in acrylic copolymer membranes in diabetic mice.
Graft survival and function without rejection due to immune cell exclusion.

28. Early Exposure to Alloantigens Studies suggest that early exposure to alloantigens can induce specific tolerance.
Example: cattle twins sharing a placenta accept grafts from each other throughout life.
Mouse experiments demonstrate tolerance induction through neonatal exposure to alloantigens .
Potential application in humans, with anecdotal evidence supporting the concept.

29. Immune tolerance to allografts can occur through privileged sites or induced biological tolerance.
Understanding mechanisms of tolerance induction may improve transplant outcomes.

30. Clinical Transplantation Importance: Only therapy for certain illnesses. Key Transplants: Kidney, liver, heart, lung, pancreas, bone marrow. Statistics: Kidney: ~400,000 transplants. Liver: ~52,000 transplants. Heart: ~42,000 transplants. Lung: ~6,000 transplants. Pancreas: ~2,000 transplants. Bone Marrow: ~80,000 transplants.

31. Advancements: 👉Improved with better medical procedures and immunosuppressive drugs.
👉Drugs help short-term survival but don’t prevent chronic rejection. Challenges: 👉Medical complications from immunosuppressive drugs.
👉Organ shortages exacerbated by the need for re-transplants after rejection.

32. Factors Influencing Transplant Frequency: 👉Clinical necessity.
👉Organ/tissue availability.
👉Complexity of the procedure and care.
👉Factors affecting transplant acceptance. Urgency of Transplants: 👉Heart, lung, liver: Immediate need, no alternatives. 👉Kidney : Dialysis can maintain patient while waiting for a transplant.

33. Kidney Transplantation The kidney is the most commonly transplanted organ.
In 2000, 13,258 kidney transplants were performed in the U.S.
Common diseases leading to kidney transplants include diabetes and nephritis.
Kidneys can be donated by both cadavers and living donors.
In 1999, 4,457 out of 12,483 kidney transplants in the U.S. Came from living donors.

34. Kidney transplantation is technically simpler compared to liver or heart transplants.
Extensive experience has led to well-developed patient-care procedures for kidney transplants.
Blood and tissue matching is crucial due to the kidney’s heavy vascularization.
Kidneys do not pose special problems of rejection or graft-versus-host disease like bone marrow or liver transplants.

35. Major challenges for kidney transplant patients include a shortage of available organs and sensitization after a first transplant.
Rejection of a first transplant can lead to antibody and cellular mechanisms against future transplants.
Detailed tissue typing is essential to avoid rejection of a new kidney.
Kidney-transplant patients usually need lifelong immunosuppression.
Immunosuppression can lead to complications such as cancer, infection, hypertension, and metabolic bone disease.

36. Bone marrow Transplants This therapy used for number of malignant and non malignant hematologic diseases include: Leukemia , Lymphoma, Aplastic anemia , Thalassemia major, Immunodeficiency diseases ( e.g.,severe combined immunodeficiency or SCID) Procedure: Obtained from a living donor by multiple needle aspirations
Consists of various blood cell lineages
Transplant typically involves injecting 10^9 cells per kilogram of host body weight intravenously

37. Requires immunological suppression of recipient pre-transplant Leukemia patients are often treated with cyclophosphamide and total body irradiation to kill all cancerous cells.
Donor Matching: Tissue-typing procedures help find HLA-identical or near-identical donors
Identical twin transplants are ideal, but allogeneic donors are common Complications include,:Graft-versus-host disease (GVHD) occurs in 50%-70% of cases

38. Donor T cells attack host cells
Causes inflammation in skin, GI tract, and liver
Severe cases can lead to skin erythroderma, GI hemorrhage , liver failure. Immunosuppressive drugs (e.g., cyclosporin A, methotrexate) Partial T-cell depletion in donor marrow to balance GVHD and graft rejection Low-level GVHD can be beneficial in preventing leukemia recurrence and graft rejection

39. Heart transplantation It is a complex and dramatic procedure.
During the operation, patients rely on heart-lung machines to circulate and aerate blood.
Donor hearts must be kept viable in ice-cold buffer solutions to prevent damage.
The first successful heart transplant was performed by Dr. Christian Barnard in South Africa, 1964.
One-year survival rate for heart transplants is over 80%.

40. In 2000, 2172 heart transplants were performed in the USA and about 3500 worldwide.
A new type of atherosclerotic disease can develop in the coronary arteries of the transplanted heart, possibly due to host antibodies.
Donor hearts are typically sourced from accident victims who are brain dead but have a functioning circulatory system.
HLA matching is ideal but often not possible due to the limited supply of hearts and the urgency of the procedure.
Heart transplants significantly benefit patients with severe heart disease, but the number of available hearts is limited.

41. Lung Transplants Lung transplants are becoming more common.
They treat diseases like cystic fibrosis, emphysema, and acute lung damage (e.g., from smoke inhalation).
In 2000, there were 945 lung transplants and 47 heart/lung transplants.
The first-year survival rate for lung transplants is approximately 60%

42. Liver Transplants The liver is a large organ and is responsible for clearance and detoxification of chemicals and biological substances. Malfunctions can be caused by viral diseases (e.g., hepatitis) or harmful chemicals (e.g., alcohol). The liver can regenerate if the damaging agent is removed. Failure to regenerate can be fatal. Liver Transplants are Mainly used to treat congenital liver abnormalities. Technical challenges due to the liver's size and complex circulation have been overcome.

43. One-year survival rate for liver transplants is about 65%.
In 2000, there were 4,816 liver transplants in the US.
Livers from a single donor can be split for two recipients (usually a child and an adult). Immunology of Liver Transplants: The liver resists hyperacute antibody-mediated rejection.
Transplantation across blood-group barriers can be successful short-term.
Mismatched blood groups can lead to hemolysis (destruction of red blood cells) in the recipient.
Graft-versus-host disease (GVHD) can occur due to donor lymphocytes, even with blood-group compatibility.

44. Pancreas Transplantation Diabetes Mellitus is A common disease in the U.S. Caused by malfunctioning insulin-producing islet cells in the pancreas.
Pancreas Transplant Offers a potential cure by providing regulated insulin levels.
One-year success rates for pancreas transplants are around 55%.
Only the islet cells need to be transplanted to restore insulin production.

45. Kidney Failure is a common complication of advanced diabetes, affecting about 30% of diabetics.
In 2000, there were 420 pancreas transplants and 904 simultaneous kidney/pancreas transplants.
University of Wisconsin Study: Achieved 87% one-year survival and 78% five-year survival in 381 cases of dual transplants.
Whether to perform simultaneous or separate kidney and pancreas transplants is determined on a case-by-case basis.

46. Skin Transplantation Skin grafts are used to treat burn victims. Most skin grafts come from the patient's own body (autologous tissue). In severe burns, grafts of frozen foreign skin from tissue banks may be used. These grafts act as biological dressings. The cells in these grafts are not alive, so the grafts do not grow in the host. These grafts are left in place for several days and regularly replaced. True allogeneic skin grafting uses fresh, viable donor skin. Requires immunosuppressive therapy to prevent rejection. Immunosuppressive therapy increases the risk of infection, which is a major concern for burn victims. The field of transplantation is growing and includes new types of transplants. For example, intracerebral neural-cell grafts have helped restore function in Parkinson’s disease patients. These neural cells come from human embryos, but using cells from other species is being tested.

47. Xenotransplantation The shortage of donor organs results in many patients dying while waiting for transplants.
Xenotransplantation:
Using nonhuman animals as organ donors for humans is being explored as a solution.
Primate Transplants;Chimpanzees and baboons have been the main donors. Early attempts at transplanting chimpanzee kidneys into humans began in 1964.

48. 1993: Two baboon liver transplants; both patients died (one after 26 days, another after 70 days).
1994: A pig liver was transplanted into a patient; it functioned for 30 hours before rejection.
1995: Baboon bone marrow was infused into an HIV-infected man; it did not establish itself but caused no complications. Xenotransplants often face vigorous immune rejection.
Potent immunosuppressive drugs like FK506 and rapamycin are used, but rejection still occurs.

49. Hyperacute rejection reaction involves humoral antibody and complement action.
Risk of spreading diseases from donor animals to human recipients ( xenozoonoses ).
Certain primate viruses can be deadly to humans (e.g., relatives of HIV-1, HIV-2, and herpesvirus B).
Primate retroviruses (e.g., SIV) may recombine with human viruses to create new diseases.
Risk of new virus introduction is higher with closely related species like primates, lower with distantly related species like pigs.

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