Transplant and Tumour immunology 05.08.25.pptx

transplant and tumor immunology

1. Immunological Mechanisms of Transplantation, Immunohematology, and Tumor Immunity   Dr. Krithikaa Sekar, MBBS, MD(Micro), MSc ( Inf.Dis.LSHTM ). PGDCR. Asst. Prof Microbiology Saveetha Medical College and Hospital

2. A. IMMUNOLOGY OF TRANSPLANTATION

3. CLASSIFICATION OF TRANSPLANTS

4. CLASSIFICATION OF TRANSPLANTS 3. Based on whether transplants are from fresh tissues and organs or from stored ones, or whether they are from living or dead materials (cadaveric transplants) Vital grafts—live grafts Structural (static) grafts—non-living transplants 4. Based on the genetic (and antigenic) relationship between the donor and the recipient, Autograft —an organ or tissue taken from an individual and grafted on the same person Isograft —a graft taken from an individual and introduced into another individual of the same genetic constitution, Allograft (formerly called homograft)—grafts between two genetically non-identical members of the same species Xenograft (formerly called heterograft)—grafts between members of different species.

5. MAJOR HISTOCOMPATIBILITY COMPLEX (MHC) Histocompatibility antigens ( alloantigen) : cell surface antigens that induce an immune response leading to the rejection of a llografts F ound on the surface of leukocytes Human MHC antigens are synonymous with human leukocyte antigens (HLA)

6. MAJOR HISTOCOMPATIBILITY COMPLEX (MHC) MHC restriction T cell can accept the processed antigen only if it is presented by a macrophage carrying on its surface the self-MHC antigens : MHC restriction . Cytotoxic T cells can recognise class I MHC antigens on the target cells. Helper T cells can accept antigens presented by macrophages/dendritic cells only when they bear the same class II MHC molecules on the surface.

7. HISTOCOMPATIBILITY ANTIGENS Antigens that participate in graft rejection are called transplantation or histocompatibility antigens Major histocompatibility system in human beings is the human leukocyte antigen (HLA) system Eichwald – Silmser effect While transplants between members of a highly inbred strain of animals are successful, an exception is seen when the donor is a male and the recipient a female. Such grafts are rejected as the grafted male tissue (XY) will have antigens determined by the Y chromosome which is absent in the female (XX) recipient. Grafts from the female to the male will succeed. This unilateral sex-linked histoincompatibility is known as the Eichwald – Silmser effect.

8. TRANSPLANTATION REACTION First-set response: Brought about by T lymphocytes. Sensitisation phase: antigen-reactive lymphocytes of the recipient proliferate in response to the alloantigen on the graft. Effector stage (second-set response): immune destruction of the graft. Fig. 19.1 Mechanism of graft rejection initiated by allogeneic immune response—sensitisation of the immune cells followed by effector mechanism leading to acute or chronic rejection

9. TRANSPLANTATION REACTION

10. IMMUNOLOGICAL BASIS OF ALLOGRAFT REJECTION Fig. 19.2 First set rejection: Blood vessels within the graft are occluded by thrombi, the vascularity diminishes and the graft undergoes ischemic necrosis 2-3 Days Graft vascularised and healthy 4-10 Days Invasion by lymphocytes & macrophages, enhanced inflammaion After 10 Days Thrombosis, ischemic necrosis & sloughing of graft Skin graft on a genetically unrelated animal of the same species 1. First set response

11. 2. Second set response In cases of first graft rejection, the second graft from the same donor will be rejected in an accelerated fashion; here, cell-mediated immunity and antibodies are actively involved in quick graft rejection Fig. 19.3 Second set rejection- the reactions are rapid with the involvement of antibodies & cell-mediated immunity, resulting in rejection of the graft IMMUNOLOGICAL BASIS OF ALLOGRAFT REJECTION

12. IMMUNOLOGICAL BASIS OF ALLOGRAFT REJECTION Hyperacute rejection (white graft response) Graft becomes pale (white graft) and is rejected rapidly It occurs in a host with high titres of pre-formed anti-donor antibodies, wherein activation of complement and cell mediated immune response results into microthrombi and occlusion of vessels Can occur in human recipients of kidney transplants, with prior transplantation, transfusion or pregnancy

13. IMMUNOLOGICAL BASIS OF ALLOGRAFT REJECTION

14. IMMUNOLOGICAL BASIS OF ALLOGRAFT REJECTION Acute rejection It occurs due to incompatibility of the allograft within 7–10 days after transplantation Graft is rejected due to accumulation of lymphocytes, plasma cells, macrophages and neutrophils, leading to endothelial damage and necrosis  

15. IMMUNOLOGICAL BASIS OF ALLOGRAFT REJECTION Chronic rejection Rejection occurs after 60 days or more, often superimposed by acute changes initiated by infiltration of granulocytes and onset of fibrosis Example: Kidney transplantation ― there is mesangial cell proliferative glomerulonephritis and interstitial fibrosis

16. Graft mounts an immune response against antigens of the host. It occurs when: Graft contains immunocompetent T cells Recipient possesses transplantation antigens that are absent in the graft Recipient is incapable of mounting an effective response against the graft Common in stem cell therapy in bone marrow transplants. Two types: ( i ) acute and (ii) chronic GRAFT-VERSUS-HOST REACTION (GVH)

17. GRAFT-VERSUS-HOST REACTION (GVH) A cute or fulminant form: W ithin the first 10 to 100 days post-transplant Chronic GVH occurs over three months to two years Examples of situations leading to the GVH reaction • Allograft in a recipient in whom specific immunological tolerance has been induced • Adult lymphocytes injected into an immunologically deficient recipient in whom the deficiency is due to immaturity ( newborn ) or immunosuppression • F 1 hybrid receiving a transplant from any one parental strain

18. GRAFT-VERSUS-HOST REACTION ( GVH ) Runt disease: It is a fatal GVH reaction in animals with emaciation, diarrhea, anemia, hepatosplenomegaly and lymphoid atrophy Fig. 19.5 Mechanism of graft-versus-host reaction in three phases of ( i ) recipients’ conditioning, (ii) donor’s T cell activation and the (iii) effect

19. Blood group testing and HLA typing are important in assessing HLA compatibility before transplantation Methods of HLA typing Micro-cytotoxicity test   Molecular methods: Restriction fragment length polymorphism (RFLP), Southern blotting & polymerase chain reaction (PCR) amplification 1. HISTOCOMPATIBILITY TESTING LAB TESTS REQUIRED BEFORE TRANSPLANTATION

20. LAB TESTS REQUIRED BEFORE TRANSPLANTATION Applications of HLA typing - Transplantation - Paternity - Anthropological studies - Genetic predisposition to disease 2. TISSUE MATCHING   Mixed lymphocyte reaction or culture (MLR and MLC)

21. IMMUNOSUPPRESSION FOR SUCCESSFUL TRANSPLANTATION I mmunosuppression of the recipient is required to inhibit r ejection I mmunosuppressive drugs : - Corticosteroids (prednisolone) Azathioprine , c yclosporine Cyclophosphamide , t acrolimus Tissue engineering has a promising role in transplantation

22. Allografts survive, safe from immunological attack in some privileged sites, e.g., fetus, cartilage, testes & cornea Probable survival mechanisms: Placenta acts as an immunological barrier by generating a locally immunosuppressive hormone Lower densities of major histocompatibility complex (MHC) antigens on trophoblastic cells Relatively resistant to attack by T or NK cells PRIVILEGED SITES

23. PRIVILEGED SITES Blocking of aggressive T cells by antigens shed by fetus Mucopolysaccharide barrier around trophoblastic cells The high concentration of alpha-fetoprotein in fetal blood which has immunosuppressive properties Areas in which a lymphatic drainage system is absent (e.g., brain) or ineffective (e.g., testes) can accept allografts without rejection

24. OTHER SOURCES OF TRANSPLANTS Fetal stem cells Adult stem cells can also be used, e.g., hematopoietic stem cells in bone marrow transplant in hematological malignancies. Non-human ( xeno ) transplants are still in the experimental stage

25. POST- TRANSPLANT INFECTIONS R isk of infection in a transplanted patient depends o n Immunosuppression (determines susceptibility) Exposure to microbial agents Depending on the status of the recipient i ) Early infection which may be related to: Healthcare-associated infections Donor-associated infection Recipient colonisers By bacteria ( staphylococci) and yeasts ( Candida species)

26. ii) Second phase: N ext 3–6 months Viruses: CMV, EBV, herpes simplex virus (HSV), human herpes virus 6, HBV and HCV Fungi: Aspergillus , Pneumocystis jirovecii Parasites: Toxoplasma and Strongyloides iii) Late onset (>6 months) : Community-acquired infections Chronic or progressive viral infections—HBV, HCV,CMV, EBV, and papillomavirus Secondary effects of viral infection POST- TRANSPLANT INFECTIONS

27. B. IMMUNOEMATOLOGY ABO system The ABO system consists of four blood groups and is determined by the presence or absence of two distinct antigens, A and B, on the surface of erythrocytes Serum contains isoantibodies specific for antigen that is absent in red cell Red cells Serum Group Antigen present Agglutinated by serum of group Antibody present Agglutinates cells of group A A B, O Anti-B B, AB B B A, O Anti-A A, AB AB A and B A, B, O None None O None None Anti-A and anti-B A, B, AB Table 19.1 Distribution of ABO antigens and antibodies in red cells and serum

28. IMMUNOHEMATOLOGY H antigen: Red cells of all ABO groups possess a common (universal) antigen, the H antigen; this antigen is not ordinarily important in grouping or blood transfusion Bombay/OH blood group: Here, A and B antigens as well as H antigens are absent from red cells; these individuals have anti-A, anti-B and anti-H antibodies and their sera are incompatible with all red cells except with same blood group (Bombay blood)

29. Rh Blood Group System An anti-Rh factor antibody is present in the RBCs of most individuals; Rh factor (Rhesus monkey) is an antigen that reacts with rabbit antiserum to Rhesus monkey erythrocytes; ‘hemolytic disease of the newborn’ is known to occur due to Rh sensitisation Typing of persons as Rh-positive or -negative depends on the presence or absence of antigen D (Rho) on red cells

30. Blood transfusion For routine blood transfusion practice, only ABO and Rh antigens matching are advised Choice of donor Ensuring that the recipient’s plasma does not contain antibodies against donor’s RBCs and donor plasma does not have antibodies that will damage the recipient’s red cells is important O blood group: ‘ universal donor ’ AB group: ‘ universal recipient ’ MEDICAL IMPLICATIONS OF BLOOD GROUP ANTIGENS

31. MEDICAL IMPLICATIONS OF BLOOD GROUP ANTIGENS Dangerous O groups: Some O group plasma may contain isoantibodies in high titres (1:200 or above), which results in damage to the recipient’s cells Rh compatibility is important only when the recipient is Rh-negative Cross-matching: It is necessary to perform cross-matching before transfusion to ensure that the donor’s blood is compatible with the recipient’s blood Coombs cross-match: D etects all incompatibilities including incomplete antibodies

32. MEDICAL IMPLICATIONS OF BLOOD GROUP ANTIGENS Hemolytic disease of the newborn Pathogenesis: Sometimes when an Rh-negative woman carries an Rh-positive fetus, she is sensitised against the Rh antigen by minor transplacental leaks at first the pregnancy; the first child usually escapes harm; however, during a subsequent pregnancy, Rh antibodies of the IgG class pass through the placenta and damage the fetal erythrocytes; for this reason, Rh typing is part of routine antenatal screening Clinical features: Accentuation of physiological jaundice, erythroblastosis fetalis, intrauterine death due to hydrops fetalis

33. MEDICAL IMPLICATIONS OF BLOOD GROUP ANTIGENS Detection of Rh antibodies Rh antibodies can be IgG (incomplete) or IgM (complete) types IgG anti-D antibodies may be detected by Using a colloid medium such as 20 per cent bovine serum albumin Using red cells treated with enzymes such as trypsin, pepsin, ficin or bromelin Indirect Coombs test (most sensitive)

34. MEDICAL IMPLICATIONS OF BLOOD GROUP ANTIGENS Treatment When diagnosed antepartum, treat with intrauterine transfusion with Rh negative blood Sometimes, premature delivery followed by transfusion and when baby is born with hemolytic disease, exchange transfusion with Rh-negative ABO-compatible blood is suggested

35. COMPLICATIONS OF INCOMPATIBLE BLOOD TRANSFUSION Clumping of RBCs & intravascular hemolysis, extravascular lysis Symptoms: Shivering, tingling sensation, excruciating headache, constricting precordial discomfort and severe lumbar pain, hypotension, cold and clammy skin, cyanosis, feeble pulse, etc.; jaundice, hematuria, oliguria and anuria may follow Reactions due to immunological processes: Rigor, urticaria and other severe hypersensitive reactions due to hemolysed or contaminated blood transfusion

36. C. IMMUNOLOGY OF MALIGNANCY (TUMOR IMMUNITY) A tumour can act as an allograft and induce immune response since they acquire new surface antigens Clinical evidence of immune response in malignancy Studies indicate the presence of an immune response which can prevent, arrest and cure malignancies Spontaneous regression : N euroblastoma and malignant melanoma

37. Chemotherapy is effective in choriocarcinoma and Burkitt’s lymphoma; some tumours overcome defence mechanism and present clinically The cellular response resembles that seen in the allograft reaction; tumours showing such cellular infiltration have a better prognosis than those that do not Immunodeficiency states are known to have a high incidence of malignancy, e.g., HIV/AIDS IMMUNOLOGY OF MALIGNANCY

38. TUMOUR ANTIGENS TUMOR-SPECIFIC ANTIGENS Tumour-specific transplantation antigens ( TSTA )/t umour-associated transplantation antigens (TATA) Found in malignant cells but absent in the normal cells They induce immune response when tumour is transplanted in syngeneic animals

39. ii) Tumour-associated antigens : Oncofetal antigens are fetal antigens, which are found in embryonic and malignant cells but not in normal adult cells are tumour-associated antigens Carcinoembryonic antigen is detected in many patients with metastatic carcinoma of colon, higher levels of alpha-fetoprotein are found in hepatic carcinoma; these antigens may have diagnostic value

40. TUMOUR ANTIGENS Differentiation antigens (prostate-specific antigen-PSA), may be higher in patients of prostate cancer and can be a diagnostic indicator Similarly, CA125 (cancer/carbohydrate antigen 125) is widely used as a diagnostic and prognostic marker of ovarian cancer

41. IMMUNE RESPONSE IN MALIGNANCY Humoral immunity May not be protective; may even be detrimental due to its facilitation of tumour growth by the process of enhancement Anti-TSTA antibodies can be demonstrated by indirect membrane immunofluorescence & delayed hypersensitivity to tumour antigens by skin test Cell-mediated immunity (CMI) CMI is considered to be protective against malignancy

42. Fig. 19.6 Interaction of T and B cells with tumour cells

43. Immunological surveillance involves to ‘ seek and destroy’ the malignant cells arising by somatic mutation Deranged surveillance mechanism due to ageing or in congenital or acquired immunodeficiencies leads to increased incidence of cancer Mechanisms Rapid proliferation rate of malignant cells may help them to ‘sneak through’ before an effective immune response A large tumour mass may be beyond the scope of immunological attack IMMUNOLOGICAL SURVEILLANCE

44. IMMUNOLOGICAL SURVEILLANCE Circu l ating tumour antigens may act as a ‘smokescreen’ coating the lymphoid cells and prevent them from acting on the tumour cells Low immunogenicity of some tumours may suppress CMI Low levels of class I MHC molecules may not be recognised by CD8 + CTLs for destruction

45. IMMUNOTHERAPY OF CANCER Passive immunotherapy Treatment with specific antisera can help in regression of tumours by neutralising the circulating tumour antigens and permitting the sensitised lymphocytes to act on tumour cells. Monoclonal antibodies to tumour antigens may play a role as carriers in transporting cytotoxic or radioactive drugs specifically to the tumour cells Specific active immunotherapy Purified tumour cell membrane antigens Tumour cells treated with neuraminidase

46. Non-specific active immunotherapy BCG and non-living Corynebacterium parvum for malignant melanoma and intradermal recurrence of breast cancer following mastectomy Dinitrochlorobenzene has been used in the treatment of squamous and basal cell carcinoma of the skin Glucan from microorganisms, and levamisole, originally introduced as an anthelmintic, have been used to stimulate CMI and macrophage function Interferons have been employed in the treatment of leukemias

47. Immunotherapy Of Cancer Specific adoptive immunotherapy Lymphocytes from persons cured of their neoplasms or specifically immunised against the patient’s tumour and lymphokine-activated killer (LAK) cells are used in renal carcinomas Immunomodulation Immunomodulators have the ability to stimulate natural and acquired defence mechanisms, such as cytokines, which enable the immune system to help itself Immunosuppressive agents and Immunostimulants