Transplantation and Autoimmunity PDF

TRANSPLANTATIO N AND HYPERSENSITIVIT Y TYPE IV Learning aims and outcomes In these videos I aim to cover: The basis and basics of transplantation science. Forms of rejection of transplants. The theoretical basis of autoimmunity and autoimmune disease. By the end...

TRANSPLANTATIO N AND HYPERSENSITIVIT Y TYPE IV Learning aims and outcomes In these videos I aim to cover: The basis and basics of transplantation science. Forms of rejection of transplants. The theoretical basis of autoimmunity and autoimmune disease. By the end of these video you should be able to: Explain the basics of transplantation and technology / procedures capable of delaying transplant. Explain the pathogenesis of transplantation rejection and hypersensitivity type IV reactions. Explain how autoimmunity can develop into autoimmune disease. Contents Transplantation and rejection Transplantation Theory Transplant rejection Hypersensitivity and transplant rejection Autoimmune Disease Theory of Development of Autoimmune Disease Disease and Treatment of Autoimmunity Transplantation theory Learning objectives Define what transplant is and learn about the types of transplants and donors. Learn what types of conditions can require transplantation. How patients can be kept alive prior to transplantation, and the matching requirements for their eventual transplant. Transplantation Definition: The process of taking an organ or living tissue and implanting it in another part of the body or another body. Types of transplant Autologous: Donated material is derived from the recipient (recipient and donor are the same person). Allogeneic Donated material is derived from a separate individual (recipient and donor are different people). Altruistic Donor continues to live after transplantation (living donor). Cadaveric donor Donor is brain dead when donating (deceased donor). Tissues and organs that can be donated Cornea Kidney Skin Hand Thymus Face Lungs Ovaries Heart Uterus Liver Haematopoietic stem cells (Bone marrow) Pancreas Bone Small intestine Ovaries Large intestine Some donations are altruistic only, some are cadaveric only and some are both. But which are which? Reasons for transplant Congenital Acquired Malignancy Dysfunction Metastatic cancer Polycystic Kidney Disease, CGD, Accident or incident Dysmorphic appearance Road traffic accidents Dextrocardia, amyloidosis, cardiomyopathy Lifestyle Absent organs Alcoholism, smoking, etc Thymus (Di George Syndrome) Acquired disease Certain diseases limiting function Hepatitis CF, Buying time for transplant Not all donations are given before the organ fails Organ transplant required for organs when function is required for life E.g. appendectomy, splenectomy. What can be done to prolong patient’s lives? Dialysis; (Haemodialysis, peritoneal dialysis), Berlin Heart Berlin heart diagram Quality of life transplant taken from: https://www.wsj.com/a Non-life threatening rticles/SB1000142405 311190429250457648 Ovarian transplant, skin graft etc. 2350886055130 Allogeneic transplant Risks of transplant Relapse of disease Potential for reintroduction of disease (from graft or metasteses) Chemotherapy resistance within leukaemic stem cell population Management of Rejection of transplant Control of immune response against the graft ATG Steroids Monoclonal antibody therapy (Alemtuzumab, Rituximab). Removal of graft? Matching patients to organs 1. Donor must be microbiologically clear (can be pre or post donation) HIV, Hep B, C and E, HTLV, Syphilis 2. Matching based upon specific organ requirements Cornea vs lung or liver Mismatch increases risk of rejection Matching includes: ABO groups, HLA tissue types (Class I and class II), CMV status, EBV status, bacteriology sampling 3. Fresh organs Locality of donor to recipient, Retrieval to transplant, can be time limited. Summary What transplants require provision by specific types of donation and donor. How symptoms of pathology can be abated through transplant. How transplants are matched to recipients in an effort to provide long- term viability to the graft and patient. Transplant rejection (Hypersensitivity type IV reactions) Learning objectives Be familiar with various types of transplantation rejection and how they present Have a basic understanding of what causes the different forms of rejection and how they are mediated. How treatments can exacerbate disease and how transplant can be used to treat and or cure malignancy. How to predict and prevent rejection Matching criteria: Can determine nature and type of rejection Tissue typing (physical and DNA analysis) Antigen mis-matches Can cause reaction Accelerates reaction Preventing rejection Lowering immune burden (stem cells) Immunosuppressive drugs (determined by patient condition and transplanted organ). Types of rejection Hyper acute-rejection Appears instantaneously Causes immediate cell death, mediation of complement ABO, group mismatch Rare from of rejection Acute rejection Shows weeks after transplant Antibody mediated Form of Graft versus Host Disease (GvHD) HLA sensitisation Targeting mismatch Can be Type II or type III hypersensitivity Chronic rejection Type IV hypersensitivity Occurs months after transplant 5 year post transplant survival rate for grafts (approx. 40-50%) Chronic rejection Cell mediated rejection C8+, fibrosing and scarring rejection Transplant in malignancy Haematopoietic cancers Chronic Lymphocytic Leukaemia, Diffuse Large B-cell Lymphoma, Myeloma Leukaemic stem cells Bone marrow niche and lymph nodes Reservoir of disease Chemotherapeutic management Radiology management Chemotherapy management Autologous transplant Aim of Chemotherapy and radiotherapy, reduce evidence of disease Bulk of disease in organ / tissue Presence of blasts in blood Cytogenetic remission (disease becomes undetectable) Overall aim Remission Disease remission Cytogenetic remission Function of chemotherapeutics Where they work How they work Malignancy and transplant Autologous Only available to certain tissue types e.g. HSC, skin grafts etc. HSCT, sources Bone marrow, apheresis or umbilical cord blood High dose chemotherapy Chemotherapy to remove leukaemic stem cells Haematopoietic stem cell transplant Given as a rescue therapy Summary How rejection and or relapse can be predicted and the form that the rejection can take. The definition of the various types rejection and their symptoms / signs. How treatments can exacerbate conditions and potentially malignancy. Hypersensitivity and transplant rejection Learning objectives The various forms of transplant rejection and their immunological causes Type II hypersensitivity in rejection Detection of antigen mis-match HLA modulated HLA-antibodies can be present ahead of transplant Type of test can generate mis-match Increase in antibody level; repeated exposure Type III hypersensitivity in rejection Serum sickness Secretion of antigen into blood stream Localised inflammation, Activation of complement C3a, C5a, Results in systemic inflammatory response Deposition of lysed material on epithelial cells Demonstration of inflammation away from the graft. Type IV hypersensitivity Cell mediated reaction Localised inflammation at site of graft Increase in immune activity Inflammation and inflammatory mediators TNF-α, TNF-β and IL-6 Epithelial damage (clotting and inflammation) Leading to granuloma formation Healing and repair Scarring End Result? Summary How transplant rejection is mediated through its various forms. Autoimmune disease Learning objectives In these videos I aim to cover: The basics of how autoimmune disease is formed. The cells involved in causing and perpetuating autoimmune disease. The laboratory’s involvement in the diagnosis and treatment of autoimmune disease As a result of these videos you should be able to explain: The basic causes of autoimmune disease and the cells associated with it. The general role of inflammation in autoimmune disease. How autoimmune can be detected and treated. Contents Theory of development of autoimmunity Disease treatment and autoimmunity. Theory of development of autoimmunity Learning objectives Understand the basic reasons as to why autoimmune disease occurs. Take a look at the basic roles cells have in generating autoimmune disease. Understand on a rudimentary basis the role inflammation has on the generation of autoimmune disease. Cause of autoimmune disease Congenital predisposition Certain genes and immune related signalling FoxP3 IL-2 receptor Fas and Fas Ligand (TNF receptor family) Understanding of how these work together is currently unknown Environmental factors can include: Diet (high fat, high salt) Infection: Viral (EBV, HTLV) Medication (Mutagenic Chemotherapeutics) T-cells and autoimmunity Loss of immune tolerance Anergic T-cells? Self reactive cells Disruption of normal immune function from APCs? Presentation of self antigen as foreign Persistence of apoptotic products? Break-down of anti-inflammatory markers on phagocytosis Induction of Defective effector immune cells? Infection of B-cells and induction to aberrant behaviour Inflammation and autoimmunity CD4+ T-cells to Th17 cells Th17+ IL-10+ cells. Mucosal lining of the gut role in suppression of inflammation Poor diet -> inflammation ^inflammation = anti-inflammatory down regulation ^inflammation = infection further inflammation = more apoptosis Th17 cells TH17 cells derived from CD4+ cells Have a pro and anti-inflammatory role Anti-inflammatory use along with T-regs (IL-10 and TGF-β) Inflammatory role GM-CSF producer RBPJ (notch signalling) Bone marrow niche theory. When generation of disease pathway is clear Treatment of HIV HIV infection affects CD4+ cells and macrophages HIV present in the blood = potential for growth of viral copies Reduction of HIV in the blood = less potential to grow Prevent spread of disease Viral load = undetectable Prevention of infection (PrEP) Sexual contact without HIV status being known is illegal Prevention of escalation of disease  When generation of disease pathway is unclear Generation Inflammato Immune Cause of of ry process response disease? antibodies Summary How environmental factors and genetic risks can both be implicated in the formation of autoimmune disease. How various cells are implicated are implicated in the perpetuation of autoimmune disease. The role of inflammation in autoimmunity. Disease and treatment of autoimmunity Learning objectives How autoimmunity can be detected using certain tests How autoimmune disease can be treated. Diagnosing autoimmune disease Demonstration of disease Colonoscopy MRI Target final antigens; Specific targets of antibodies generate specific disease Immunohistochemistry ELISA Specific Binding patterns demonstrate antigen specificity Antigen specificity highlights type of autoimmunity and disease Treatment of autoimmunity Immunosuppression Lowering immune system overall lowers autoimmunity Steroids (reduce inflammation) MAbs Chemotherapy Strengthening area of degradation Physiotherapy, Vitamin D therapy Stem cell Transplant Reset immune system to an earlier point Not curative, can delay progression. Summary The role of certain tests in the diagnosis of autoimmune disease. How treatments can be used to reduce the symptoms, signs and burdens of autoimmune disease.