Published on March 9, 2014
PowerPoint Presentation: Immunology of Transplantation ad Malignancy Dr. Pendru Raghunath Reddy PowerPoint Presentation: Definition Transplantation refers to the act of transferring cells, tissues or organs from one site to another The tissue or organ trasplanted is known as the transplant or graft The individual from whom the transplant is obtained is known as the donor and the individual to whom it is applied, the recipient or host PowerPoint Presentation: Can you imagine? Types: Types Autologous graft ( autograft ) : Self-tissue transferred from one body site to another in the same individual Examples 1. Transferring healthy skin to a burned area 2. Use of healthy blood vessels to replace blocked coronary arteries Isograft : Tissue or organ tranferred between genetically identical individuals Allograft: Tissue transferred between genitically different members of the same species Xenograft : Tissue traferred between different species PowerPoint Presentation: Applications of allografting transplantation PowerPoint Presentation: Allograft reaction Rejection of the graft by the recipient is called the allograft reaction First set reponse When a skin graft from an animal is applied on a genetically unrelated animal of the same species, the graft appears to be accepted initially The graft is vascularized and seems morphologically and functionally healthy during the first two or three days By about the fourth day, inflammation becomes evident PowerPoint Presentation: The graft assumes a scab-like appearance with extending necrosis and sloughs off by the the tenth day Second set reponse When a second allograft from the same donor is applied on a sensitised recipient, it will be rejected in an accelerated fashion Necrosis sets in early and the graft sloughs off by the sixth day Antibodies play a dominant role along with cell mediated immunity First- and second-set allograft rejection: First- and second-set a llograft rejection Figure 16.1 PowerPoint Presentation: For matching donor and recipient for transplantation following procedures are undertaken ABO grouping Tissue typing (detection of MHC antigens) ( Microcytotoxicity test, Mixed lymphocytes culture (MLC) and Molecular methods) PowerPoint Presentation: Prevention of graft rejection Immunosupression 2. Transplantation in anatomically protected ( privilieged ) sites There are certain privileged sites where allografts are permitted to survive Examples: Cornea, Brain, Cartilage, Pancreatic islet cells PowerPoint Presentation: Fetus as allograft The fetus can be considered an intrauterine allograft as it contains antigens which are foreign to the mother The reason why the fetus is exempted from rejection is not clear, though many explanations have been offered The palcenta acts as an immunological barrier Mucoproteins Blocking antibodies MHC antigens Alpha fetoprotein β 1 - glycoprotein PowerPoint Presentation: Graft-Versus Host (GVH) reaction Graft rejection is generally due to the reaction of the host to grafted tissue (host-versus-graft response) Contrary to that, the graft may mount an immune response against the antigens of the host, this is known as “graft-versus-host reaction” The GVH reaction occurs when the following conditions are present The graft contains immunocompetent T cells The recipient possesses HLA antigens that are absent in the graft 3. The recipient must not reject the graft PowerPoint Presentation: The GVH reactions are predominantly cell mediated GVH is a major complication of bone marrow transplantation and affects 50 to 70% of bone marrow transplant patients Donor T cells recognise alloantigens on the host cells The activation and proliferation of these T cells and the subsequent production of cytokines generate inflammatory reactions in the skin, gastrointestinal tract and liver PowerPoint Presentation: The clinical manifestations of GVH reaction consists of splenomegaly , fever, rash, anaemia , weight loss and sometimes death The clinical manifestations of GVH reaction in animals are retardation of growth, emaciation, diarrhea, hepatosplenomegaly , lymphoid atrophy and anaemia,terminating fatally ( runting disease) PowerPoint Presentation: Tumour immunity When a cell undergoes malignant transformation, it expresses new surface antigens and may also lose some normal antigens The tumour associated antigens are immunologically distinct from normal tissue antigens Therefore, tumour can be considered as an allograft and is expected to induce an immune response Normal Cell Growth: Normal Cell Growth Control of cell growth Growth-promoting Proto- oncogenes Growth-restricting Tumor-suppressor genes Molecular Basis of Cancer: Molecular Basis of Cancer Uncontrolled cell growth Proto- oncogenes Tumor-suppressor genes Mutations Radiation Chemical (Carcinogen) Virus Etiology of tumor: Etiology of t umor 1) Inherited : Expression of inherited oncogene e.g. viral gene incorporated into host gene 2) Viral: - Human papilloma , herpes type 2, HBV, EBV (DNA) - Human T-cell leuckemia virus (RNA) 3) Chemical: - Poly cyclic hydrocarbons cause sarcomas - Aromatic amines cause mammary carcinoma - Alkyl nitroso amines cause hepatoma 4) Radiological: Ultraviolet & ionizing irradiation 5) Spontaneous: failure in the cellular growth control Tumour antigens: Tumour antigens Major Histocompatability Complex antigens TSTA TATA TSTA : unique to a tumor Play an important role in tumor rejection. TATA : shared by normal and tumor cells Tumor-associated developmental Ag (TADA) Tumor-associated viral Ag (TAVA) Tumor-specific Antigens (TSAs) Tumor-associated Antigens (TAAs) PowerPoint Presentation: Tumour specific antigens (TSAs or TSTAs) Unique to tumour cells and do not occur on normal cells in the body TSAs or TSTAs have been identified on tumours induced with chemical or physical carcinogens and on some virally induced tumours In chemically induced tumors, these antigens are tumour specific Different tumours possess different antigens, even if they are induced by the same carcinogen In contrast, the TSAs of virus induced tumours are virus specific PowerPoint Presentation: Tumour associated antigens (TAA or TATAs) These are present on tumour cells and also on some normal cells However, they are expressed at extremely low levels on normal cells but are expressed at much higher levels on tumour cells They fall into three categories Tumour associated carbohydrate antigens (TACAs) Oncofetal antigens ( alphafetoprotein , carcinoembryonic antigen) 3. Differentiation antigens PowerPoint Presentation: Immune response in malignancy Tumour antigens can induce both humoral and cell mediated immune responses that result in the destruction of the tumour cells The immune response to tumour includes CTL-mediated lysis , NK-cell activity, macrophage-mediated tumour destruction and destruction mediated by ADCC PowerPoint Presentation: NK Make up 5-10% of c irculating l ymphocytes Major producers of IFN Through IFN they influence innate immunity (M) They also influence adaptive immunity by favoring T H1 Eliminate viruses and tumor cells Early responders to viral Infections IFN and IFN stimulates NK activity IFN production induces M to make IL-12 IL-12 results in more IFN pushing towards T H1 T H1 through IL-2 Induces CTL activation Natural Killer Cells PowerPoint Presentation: NK eliminate target cells same way as CTLs Through perforin / granzyme and FasL / Fas However they are different from CTLs No Ag specific TCR No CD3 No MHC restriction No memory, same intensity regardless of repeated exposure PowerPoint Presentation: Cells capable of cytotoxicity express Fc receptors Antibody binds to target Cell, cytotoxic cells bind Fc portion of antibody Antibody provides the specificity Examples of cells capable of ADCC M , NK, Neutrophils , eosinophils Killing of target is accomplished Through perforin , granzyme (NK, Eosinophils ) TNF (M , NK) Lytic enzymes (M , Neutrophils , Eosinophils , NK) Antibody Dependent Cell Mediated Cytotoxicity (ADCC) PowerPoint Presentation: Immunosurveillance It is believed that malignant cells arise by mutation of somatic cells The immune system keeps a consant vigilance on these malignant mutation of somatic cells and destroy them on the spot The development of tumours represents an escape from this surveillance PowerPoint Presentation: Weak immunogenicity Modulation of surface antigens Masking tumour antigens Supression of CMI Fast rate of proliferation of malignant cells Production of blocking antiodies Low levels of HLA class I molecules The mechanisms of such escape are not clear but various possibilities have been suggested Escape from immunosurveillance: 34 Escape from immunosurveillance Lack of n eo-antigens Escape from immunosurveillance: 35 Escape from immunosurveillance Lack of class I MHC Escape from immunosurveillance: 36 Escape from immunosurveillance Tumors secrete i mmuno - suppressive molecules Escape from immunosurveillance: 37 Escape from immunosurveillance Production of blocking antibodies PowerPoint Presentation: Immunotherapy of cancer Different approaches have been attempted in the immunotherapy of cancer Active Nonspecific Specific 2. Passive a) Nonspecific b) Specific c) Combined PowerPoint Presentation: Nonspecific active immunotherapy Biological response modifiers (BRMs) are used to enhance immune responses to tumours and fall into four major groups 1. Bacterial products (BCG, nonliving Corynebacterium parvum ) 2. Synthetic molecules ( Glucan , levamisole ) 3. Cytokines 4. Hormones PowerPoint Presentation: Specific active immunotherapy Specific active immunotherapy includes therapeutic vaccines of tumour cells, cell extracts, purified or recombinant antigens, peptides, heat shock proteins, or DNA antigen-pulsed dendritic cells Passive immunotherapy Passive immunotherapy may be Nonspecific (LAK cells) Specific (antibodies alone or coupled to drugs, prodrugs , toxins or radioisotope, bispecific antibodies T cells) 3. Combined (LAK cells and bispecific antibody)
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