Transplantation and Hypersensitivity Type IV

Transplantation and Hypersensitivity Type IV

• Transplantation is the process of taking an organ or tissue and implanting it into another part of the body or another body.
• Types of transplants include:
  • Autologous: Donor and recipient are the same person.
  • Allogeneic: Donor and recipient are different people.
  • Altruistic: Living donor.
  • Cadaveric: Deceased donor.

Learning Aims and Outcomes

• The videos cover the basis of transplantation science, forms of transplant rejection, the theoretical basis of autoimmunity, and autoimmune disease.
• By the end of the videos, students should be able to:
  • Explain transplantation basics and delaying procedures
  • Describe 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

• A general overview or introduction to transplantation is presented.

Learning Objectives

• Define transplantation and different types of transplants and donors.
• Understand diseases requiring transplantation.
• Learn about methods to maintain life prior to transplants and matching requirements.

Types of Transplant

• Autologous transplants use the recipient's own material.
• Allogeneic transplants use material from a different person.
• Altruistic transplants use a living donor.
• Cadaveric transplants use a deceased donor who is brain dead.

Tissues and Organs that can be Donated

• This section lists possible, donated tissue and organs including cornea, skin, thymus, lungs, heart, liver, pancreas, small and large intestines, kidney, hand, face, ovaries, uterus, hematopoietic stem cells (bone marrow) and ovaries.
• Some donations are exclusively altruistic, others cadaveric, or both.

Reasons for Transplant

• Congenital dysfunctions like polycystic kidney disease, and certain dysmorphic appearances can require transplants, as well as diseases affecting organs, and genetic conditions.
• Acquired conditions like cancers, accidents, lifestyle factors such as alcoholism, and diseases like hepatitis can also be reasons.

Buying Time for Transplant

• Not all transplantations occur before the organ fails.
• Methods such as dialysis (haemodialysis, peritoneal dialysis) and devices like the Berlin Heart are used to temporarily support failing organs.
• Other quality of life transplants such as ovarian transplants and skin grafts fall into the category of non-life-threatening conditions.

Allogeneic Transplant

• Risks of relapse, potential for reintroduction of disease, chemotherapy resistance in leukemia stem cells warrant considerations.
• Treatments for transplant rejection such as ATG (anti-thymocyte globulin), steroids, and monoclonal antibodies (like Alemtuzumab, Rituximab) are used to control immune responses.

Matching Patients to Organs

• Donated organs need microbial clearance (HIV, Hep B/C/E, HTLV, Syphilis).
• Matching is based on organ specific requirements such as in cornea, lung or liver transplants.
• Factors such as ABO blood groups, HLA tissue types (Class I and II), CMV and EBV status, and bacteriology sampling are used.

Summary

• Specific donations are needed for different types of transplant requirements. Transplantation can improve symptomatic pathology. Organ matching is performed trying to ensure graft and patient long-term survivability.

Transplant Rejection (Hypersensitivity Type IV Reactions)

• The focus is on hypersensitivity (type IV reaction) relating to transplant rejection.

Learning Objectives

• Be familiar with different types of transplant rejections.
• Understand the causes and mechanisms for those rejections.
• Understand how treatments may affect malignancy and exacerbate the disease.

How to Predict and Prevent Rejection

• Tissue typing (physical and DNA analysis) is used to determine the nature and type of rejection.
• The goal is to lower the immune burden (using stem cells) and use immunosuppressive drugs, tailored to the specific patient and transplanted organ.

Types of Rejection

• Hyper-acute rejections occur immediately, often due to ABO blood group mismatches.
• Acute rejection shows up weeks later, often antibody-mediated, and can involve graft-versus-host disease (GvHD).
• Chronic rejection develops over months and involves type IV hypersensitivity, with cell-mediated rejection and fibrosing or scarring.

Acute Rejection

• This typically occurs after transplant procedures.
• It's mediated by antibodies and involves graft-versus-host disease (GvHD).
• HLA sensitization and mismatches play a crucial role in acute rejection.

Chronic Rejection

• Chronic rejection occurs months after transplantation.
• The 5-year survival rate is approximately 40-50% for transplanted organs.
• It is a cell-mediated type IV hypersensitivity reaction with scarring and fibrosis.

Transplant in Malignancy

• Transplantation is used for conditions such as chronic lymphocytic leukemia, diffuse large B-cell lymphoma, and myeloma.
• The bone marrow niche and lymph nodes can be reservoirs for the disease and are areas of focus for treatments.
• Chemotherapy and radiology are used to manage and address cancerous leukaemic stem cells in the process.

Chemotherapy Management

• The aim of chemotherapy, combined with radiotherapy, is reduced disease in organ/tissue, and removal of blasts in the blood.
• Cytogenetic remission (disease becomes undetectable) and disease remission are objectives.

Autologous Transplant in Malignancy

• Autologous transplants are specific to certain tissue types.

Summary

• Forecasting rejection/relapse, understanding rejection processes, and how treatments might exacerbate or cure malignancy are key elements to cover.

Hypersensitivity and Transplant Rejection

• This section focuses on hypersensitivity reactions related to transplant rejection.

Learning Objectives

• The focus of this section is on understanding different forms of transplant rejection and their immunological causes.

Type II Hypersensitivity in Rejection

• HLA-modulated HLA-antibodies may be present before a transplant.
• Repeated exposure can increase antibody levels.

Type III Hypersensitivity in Rejection

• Serum sickness involves antigen secretion into the bloodstream, localized inflammation, and complement activation (C3a, C5a).
• Systemic inflammatory response results from the deposition of lysed material on epithelial cells.

Type IV Hypersensitivity

• Localized inflammation at the graft site is characteristic.
• Immune activity increases, and inflammatory mediators (TNF-α, TNF-β, IL-6) are involved.
• Graft tissue damage and scarring are possible outcomes.

Summary

• Transplant rejection is mediated through its various forms (type II, III and IV).

Autoimmune Disease

• This section discusses the causes of autoimmune diseases.

Learning Objectives

• The learning objectives focus on understanding the causation and perpetuation of autoimmune diseases—including inflammatory processes.

Cause of Autoimmune Diseases

• Genetic predisposition plays a role with specific genes that could have an impact on immune signaling (FoxP3, IL-2 receptor).
• Fas and Fas Ligand (TNF receptor family) are involved.
• Environmental factors include diet (high-fat, high-salt), infections (viral, EBV, HTLV), and medication (mutagenic chemotherapeutics).

T-cells and Autoimmunity

• Concepts of tolerance loss, anergic T-cells, self-reactive cells, disruption of immune function, presentation of self-antigens, persistence of apoptotic products, disruption of anti-inflammatory markers on phagocytosis, and induction of defective effector cells are discussed.

Inflammation and Autoimmunity

• Focus is on the link between inflammation and autoimmunity.
• CD4+ T-cells and Th17 cells are highlighted, specifically Th17+ IL-10+ cells and their roll with mucosal immunity and anti-inflammation.

Th17 Cells

• Th17 cells are derived from CD4+ cells.
• Th17 cells have a role in pro- and anti-inflammatory processes.
• Anti-inflammatory factors (e.g. IL-10 and TGF-β) are included, and GM-CSF, RBPJ (notch signaling) and bone marrow niche theory.

When Generation of Disease Pathway is Clear

• HIV infection impacts CD4+ cells and macrophages.
• Present HIV in the blood means potential for increased viral copies.
• Reducing or preventing HIV spread is important.
• Prevention of infection via PrEP (pre-exposure prophylaxis) and prevention of escalation through proper sexual practices are critical elements.

Summary

• Environmental factors, genetic risks, immune cells, and inflammatory roles in autoimmune disease are all included.

Disease and Treatment of Autoimmunity

• This section discusses the diagnosis and treatment for autoimmune disorders.

Diagnosing Autoimmune Diseases

• Techniques such as colonoscopies and MRI are used to demonstrate the existence of diseases.
• Specific targets for antibodies that are generating specific diseases are identified using immunohistochemistry and ELISA techniques.

Treatment of Autoimmunity

• Immunosuppression, reducing systemic immune activity—including steroid use and monoclonal antibodies (MAbs)—are included.
• The approach also looks into treating an area of degradation (physiotherapy, vitamin D), and in severe cases, stem-cell transplants, which reset the immune system.

Summary

• The role of tests in diagnosing autoimmune disease, and the use of treatments to control symptoms and complications are covered.