Transplantation & Tumor Immunology PDF

Prepared by : ERWIN VHAL D. MEIM, RMT, MSMT  Transfer of a tissue or organ from one part of the body to another within the same person transfer of a tissue or organ from one individual to another individual Transplantation or Grafting of an organ or tissue ranges from self transplantati...

Prepared by : ERWIN VHAL D. MEIM, RMT, MSMT  Transfer of a tissue or organ from one part of the body to another within the same person transfer of a tissue or organ from one individual to another individual Transplantation or Grafting of an organ or tissue ranges from self transplantation to grafting of a body component from one species to another  AUTOGRAFT -- Graft transferred from one person to another in the same individual SYNGRAFT -- Graft transplanted between different but identical recipient and donor ALLOGRAFT (HOMOGRAFT) -- Graft between genetically different recipient and donor of the same species. In this type of transplant the grafted donor tissue or organ contains antigen not present in the recipient. XENOGRAFT (HETEROGRAFT) -- Graft between individual of different species (Please refer also to the Study Guide of Chapter 16)  DIRECT ALLORECOGNITION – – When T cells bind directly to the intact allogeneic MHC molecules on Professional APC in the graft cells INDIRECT ALLORECOGNITION – – Occurs when allogeneic molecules from graft cells are taken up and processed by recipients APC and peptide fragments of the allogeneic MHC molecules are presented by recipient’s (self) MHC molecule  TERMS DEFINING PHYSICAL PLACEMENT 1. ORTHOTOPIC – if the graft is transplanted from one place on the donor to same place on the recipient. Example of Graft : kidney, heart 2. HETEROTOPIC – if the graft is transplanted from one place on the donor to a different site on the recipient Example of Graft : skin, bone IMMUNE PRIVILEGED SITES Sites in the body where foreign tissue grafts can survive for extended, often indefinite periods of time, whereas similar grafts placed at regular sites in the body are acutely rejected. EXAMPLES : Anterior chamber of the eye, brain , pregnant uterus, testes THE EYE A PRIVILEGED SITE - The phenomenon of the so called anterior chamber-associated immune deviation (ACAID), where the antigenic material introduced into the anterior chamber of the eye elicits a systemic immune response that results in the suppression of T cell-mediated immunity, while enabling the production of non-complement-fixing antibodies (described as immune deviation) - Other mechanisms are reduced expression of MHC molecules on ocular cells, and the existence of an intraocular anti-inflammatory environment, mediated by resident cells, and various molecules, IMMUNE PRIVILEGED SITES are the places of the body that are isolated from the immune system Can be preserved by local active mechanisms that suppress responses to antigens within the privileged tissues DIFFERENT ORGANS BODY PARTS Cornea Blood vessels Heart Bone Kidneys Bone marrow or Liver stem cells Lungs Middle ear Pancreas Skin  ABO Blood Group Antigens – Are genetically determined antigens expressed on membranes of non nucleated cells, the RBC. The major problem with blood transplantation or transfusion is that most of us, except the AB blood group individuals have the antibodies (isohemagglutinins) to these antigens. Genes encoding ABO blood group are polymorphic. MAJOR HISTOCOMPATIBILITY COMPLEX – On nucleated cells, the major histocompatibility complex is the main tissue transplantation barrier. These antigens are encoded by the highly polymorphic, MHC locus. The inheritance of 2 alleles (out of many possible) at 6 different loci (e.g. A, B, C, DP, DQ, DR) denotes an extremely low chances that all HLA antigens of 2 unrelated individuals be exactly the same.  MINOR HISTOCOMPATIBILITY ANTIGENS – Are the minor transplantation which include the non ABO blood group alloantigens and antigens associated with the sex chromosomes. These are usually “weaker” than the MHC antigens and may be the antigens targeted by the immune system in late onset rejection.  TYPES OF TRANSPLANT REJECTION GRAFT REJECTION –a specific immune response to an organ or tissue graft that leads to inflammation, damage and possibly graft failure HYPERACUTE rejection – A form of allograft or xenograft rejection that begins within minutes to hours after transplantation and is characterized by thrombotic occlusion of the graft vessels. This type of rejection is mediated by preformed (pre-existing) cytotoxic Abs in the host circulation that binds to donor endothelial Ags (e.g. blood group Ag or MHC molecules) thereby causing activation of the complement system ACUTE rejection - This type involves vascular and parenchymal injury mediated by T cytotoxic cells, macrophage and antibodies that usually occurs days or weeks after transplantation. It is characterized by skin rashes, diarrhea and increased risk to infection PLEASE REFER ALSO TO STUDY GUIDE; TYPES OF GRAFT REJECTION ON PAGE 275  TYPES OF TRANSPLANT REJECTION CHRONIC rejection- an allograft rejection characterized by progressive fibrosis of blood vessel in the grafted tissue and with loss of normal organ structures occurring during a prolonged period. Major Pathologic feature : Graft arterial occlusion caused by proliferation of intimal smooth muscle and thus called graft arteriosclerosis. GRAFT VERSUS HOST DISEASE (GVHD) - A disorder that usually happens in bone marrow transplant recipients caused by the reaction of mature T cells in the marrow graft with alloantigens on host cells. Organs most often affected by GVHD are skin , liver and intestines. But for the three major types of rejection, the condition is HOST VERSUS GRAFT. Clinical presentation of Acute rejection and GVHD is similar to Type IV hypersensitivity ; Hyperacute is categorized as Type II hypersensitivity while Chronic can be both Type III and IV hypersensitivity. PLEASE REFER ALSO TO STUDY GUIDE; TYPES OF GRAFT REJECTION ON PAGE 275 TYPES OF TRANSPLANT REJECTION  Deals with the relationship between host’s immune function and tumour cells. Describes the interaction between the cells of the immune system Understanding on how the immune system works against tumour cells is crucial in the management of cancer and the development of new therapies for cancer  Abnormal mass of tissue ; Is the result of conversion, transformation of a normally dividing cell into one with uncontrollable growth. A tumour can be BENIGN OR MALIGNANT BENIGN TUMOUR MALIGNANT TUMOUR  CARCINOMA – tumour originating from the skin or epithelial linings of internal organs or glands SARCOMA – tumours arising from the connective tissue (e.g. bone, adipose tissue, cartilage, tendon, muscle) APOPTOSIS – A normal homeostatic mechanism that involves a series of biochemical reactions leading to : – A. Chromatin condensation – B. DNA fragmentation – C. Cell Shrinkage – D. Membrane blebbing TUMOR ANTIGEN TUMOR SPECIFIC ANTIGEN – Antigens that are unique to the tumor of an individual patient or shared by a limited number of patients with the same type of tumor. It is not expressed on normal cells and may serve as target antigens for anti-tumor immune responses. TUMOR ASSOCIATED ANTIGEN (aka. TISSUE SPECIFIC ANTIGEN – Antigens that are expressed by normal cells as well as tumor cells. Please refer to Table 17-1 , p 282 for the Different types of Tumor Antigens  TUMOR SPECIFIC ANTIGEN TRANSPLANTATION ANTIGEN (TSTA) – An antigen expressed on experimental animal tumor cells that can be detected by induction of immunologic rejection of tumor transplants. TUMOR MARKERS – Biological substances found in increased amounts in the blood, body fluids and tissues of patient with a specific type of cancer. Please refer to Table 17-3 p 283 for the categories of Clinically relevant Tumor Markers METASTASIS – The ability of cells to break away from the original tumor mass and spread through the blood to nearby r distant sites in the body. NEOPLASIA – the continuous multiplication of cells in the absence of a known stimulus  Clinical Applications 1. Screening 2. Diagnosis 3. Prognosis 4. Monitoring SCREENING - It provides an ideal way to screen for tumors because the markers can be detected by a simple blood test. Screening can lead to early detection of the disease DIAGNOSIS -Tumor markers help clinicians distinguish between different diseases with similar symptoms. Differential Diagnosis. PROGNOSIS -Assessment of increasing concentration of tumor markers at the time of diagnosis MONITORING -To determine whether their treatment is effective and to check for recurrence of the tumor. 1. GROSS AND MICROSCOPIC MORPHOLOGY 2. TUMOR MARKERS BY IHC 3. MOLECULAR DIAGNOSTICS 1. Mutation in Genes brought about by Physical factors- exposure to ionizing radiation, UV rays Environmental Factors e.g. cigarette smoke, exposure to chemicals such as asbestos. 2. Infection with Tumorigenic Viruses e.g. HBV, HIV, Human Papilloma viruses Please refer to Table 17-2 on p.283 for the List of Human viruses associated with Cancer 3. Expression or Conversion of Proto- oncogenes into an Oncogenes Proto oncogene – Proto-oncogenes are regulatory genes that normally aid in cell division. When a proto-oncogene mutates (changes) or there are too many copies of it, it becomes Oncogenes. Oncogenes encodes protein that induce cellular transformation. TUMOR SUPPRESSOR GENES – genes that inhibit the growth of tumors MALIGNANT TRANSFORMATION OF HEMATOLOGIC CELLS A. CELL PROPERTIES B. GENETIC CHANGES 1. LEUKEMIA 2. LYMPHOMA 3. PLASMA CELL DYSCRASIA 1. LEUKEMIA A Type of cancer that affects the blood forming tissue specifically the bone marrow The malignant cells are primarily present in the bone marrow and peripheral blood LEUKEMIA TWO GROUPS A. Myelogenous B. Lymphocytic 1. LEUKEMIA TWO GROUPS A. Myelogenous -Derived from the common myeloid precursor and encompass the granulocytic, monocytic, megakaryocytic and erythrocytic leukemias 1. LEUKEMIA TWO GROUPS B. Lymphocytic - Leukemias which originates from mature lymphocytes or their precursors 1. LEUKEMIA TWO TYPES A. CHRONIC B. ACUTE 1. LEUKEMIA TWO TYPES A. CHRONIC - SLOWLY PROGRESSIVE AND COMPATIBLE WITH EXTENDED SURVIVAL. GENERALLY NOT CURABLE WITH CHEMOTHERAPY 1. LEUKEMIA TWO TYPES B. ACUTE -RAPIDLY PROGRESSIVE AND HAS A HIGHER RESPONSE RATE TO THERAPY 1. ACUTE LYMPHOCYTIC LEUKEMIA IS CHARACTERIZED BY THE PRESENCE OF VERY POORLY DIFFERENTIATED PRECURSOR CELLS IN THE MARROW AND PERIPHERAL BLOOD. CAN ALSO INFILTRATE SOFT TISSUES, LEADING TO ORGAN DYSFUNCTION AND FAILURE 1. ACUTE LYMPHOCYTIC LEUKEMIA Usually seen in children between 2 to 5 yrs old (MOST COMMON TYPE) Treatable with a remission rate of 90% and cure rate of 80% in children. 1. ACUTE LYMPHOCYTIC LEUKEMIA FOUR TYPES 1. T-CELL 2. MATURE B-CELL 3. CD-10 EXPRESSING PRECURSOR B-CELL 4. PRECURSOR B-CELL WITHOUT CD10 2. CHRONIC LYMPHOCYTIC LEUKEMIA -GROUP OF LEUKEMIAS ALMOST EXCLUSIVELY OF B-CELL ORIGIN. TYPES 1. CLL 2. SLL 3. HAIRY CELL LEUKEMIA A RARE, PROGRESSIVE DISEASE CHARACTERIZED BY INFILTRATION OF THE BONE MARROW AND SPLEEN BY LEUKEMIC CELLS WITHOUT THE INVOLVEMENT OF THE LYMPH NODES. USUALLY SEEN IN INDIVIDUALS OER 20 YRS OLD WITH PANCYTOPENIA, SPLENOMEGALY, AND NO LYMPHADENOPATHY MALIGNANT CELLS EXPRESS B-CELL MARKERS CD19, CD20, AND CD22 LYMPHOMA -NEOPLASM OF LYMPHOID OR RET TWO TYPES 1. HODGKIN LYMPHOMA 2. NON-HODGKIN LYMPHOMA HODGKIN LYMPHOMA MOST COMMON TYPE CURABLE THAT OCCURS IN YOUNG ADULTS AND ELDERLY PERIPHERAL LN, LUNGS, LIVER, BM NON-HODGKIN LYMPHOMA 2/3 OF 60 YRS OLD AND ABOVE GREATER IN MEN IMMUNOSUPPRESION WITH GREATEST RISK NON-HODGKIN LYMPHOMA CONDITION ASSOCIATED WITH INCREASED RISK OF NHL 1. CERATIN AUTOIMMUNE DISEASES 2. CONGENITAL IMMUNODEFICIENCY DISORDERS 3. ORGAN TRANSPLANTATION 4. EXPOSURE TO INFECTIOUS AGENTS PLASMA CELL DYSCRACIAS DYSCRASIA REFERS TO THE ABNORMAL OR DISORDERED STATE OF THE BODY OR BODY PART A GROUP OF CONDITION CHARACTERIZED BY THE ABNORMAL PROILFERATION OF PLASMA CELLS, THE ANTIBODY PRODUCING CELLS. PLASMA CELL DYSCRACIAS MULTIPLE MYELOMA WALDENSTROM MACROGLOBULINEMIA SMOLDERING MM MGUS MYELOMA PROTEIN -ABNORMAL ANTIBODY OR A FRAGMENT OF IT, THAT IS PRODUCED IN EXCESS BY AN ABNORMAL MONOCLONAL PROLIFERATION OF PLASMA CELLS MULTIPLE MYELOMA MALIGNANCY OF MATURE PLASMA CELLS 10% OF HEMATOLOGIC CANCERS EXCESS PLASMA CELLS IN BM MULTIPLE MYELOMA ALSO KNOWN AS PLASMA CELL MYELOMA OVERPRODUCTION OF MONOCLONAL IGG 20% OF MYELOMA CELLS EXPRESS CD20 MULTIPLE MYELOMA CLINICAL MANIFESTATION 1. HEMATOLOGIC 2. SKELETAL 3. IMMUNOLOGIC MULTIPLE MYELOMA DEFECTS: 1. KIDNEY INJURY 2. CARDIOMYOPATHY 3. PERIPHERAL NEUROPATHY 4. HEPATOSPLENOMEGALY BENCE JONES PROTEIN MONOCLONAL LIGHT CHAINS FOUND IN THE BLOOD AND EXCRETED IN THE URINE WALDENSTROM’S MACROGLOBULINEMIA MALIGNANT PROLIFERATION OF IgM-producing lymphocytes Lymphoplasmacytoid lymphoma WALDENSTROM’S MACROGLOBULINEMIA CLINICAL SIGNS WEAKNESS FATIGUE ANEMIA BLEEDING HYPERVISCOSITY HYPERVISCOSITY -IT CAN DEVELOP WHEN THE LEVEL OF M PROTEIN IN THE PLASMA IS HIGH -SEEN IN IGM PRODUCING TUMORS