Transplantation Immunology

Transplantation

• It is the transfer of tissue or an organ from one part of the body to another within the same person or from one individual to another.
• Transplantation/grafting ranges from self-transplantation to grafting a body component from one species to another.
• The preferred treatment for end-stage organ failure because of the quality of life and long-term cost benefits it offers.
• The potential life-saving treatment for cancer, autoimmune diseases, and immunodeficiency diseases.

Types of Transplants

Based on the genetic relatedness of the donor to the recipient:

• Autograft: Graft is transferred from one person to another in the same individual.
• Syngraft: Graft is transplanted between different but identical recipients and donors.
• Allograft (Homograft): Graft is between genetically different recipients and donors of the same species
  • The grafted donor tissue or organ contains antigens not present in the recipient.
• Xenograft (Heterograft): Graft is between individuals of different species

Allorecognition Types

• Direct Allorecognition:
  • T cells directly bind to intact allogeneic MHC molecules on professional antigen-presenting cells (APCs) in the graft cells.
• Indirect Allorecognition:
  • Allogeneic molecules from graft cells are taken up and processed
  • These are processed by recipient APCs
  • Peptide fragments of the allogeneic MHC molecules are presented by the recipient's (self) MHC molecule.

Direct vs. Indirect Recognition

Transplantation Terms

Terms Defining Physical Placement:

• Orthotopic: Graft is transplanted from one place on the donor to the same place on the recipient.
  • Examples: kidney, heart
• Heterotopic: Graft is transplanted from one place on the donor to a different site on the recipient.
  • Examples: skin, bone

Immune Privileged Sites

• Body sites where foreign tissue grafts can survive for extended time periods.
  • Similar grafts placed at regular sites are acutely rejected
  • Examples: anterior chamber of the eye, brain, pregnant uterus, testes
• These sites are isolated from the immune system
  • They are preserved by local active mechanisms that suppress responses to antigens within the privileged tissues

The Eye

• Anterior chamber-associated immune deviation (ACAID) is a phenomenon
  • Antigenic material is introduced into the anterior chamber of the eye
  • A systemic immune response is triggered
  • Results in the suppression of T cell-mediated immunity
  • Enables the production of non-complement-fixing antibodies (immune deviation).
• Reduced expression of MHC molecules on ocular cells and the existence of an intraocular anti-inflammatory environment.
  • Mediated by resident cells and various molecules.

Types of Transplants

• Different Organs
  • Cornea
  • Heart
  • Kidneys
  • Liver
  • Lungs
  • Middle ear
  • Pancreas
  • Skin
• Body Parts
  • Blood vessels
  • Bone
  • Bone marrow or stem cells

Major Transplantation Antigens

• ABO Blood Group Antigens:
  • Genetically determined antigens expressed on membranes of non-nucleated cells (RBCs)
  • Most individuals, except those with AB blood type, possess antibodies (isohemagglutinins) to these antigens.
  • Genes encoding ABO blood groups are polymorphic.
• Major Histocompatibility Complex (MHC):
  • Main tissue transplantation barrier on nucleated cells.
  • Encoded by the highly polymorphic MHC locus.
  • Inheritance of 2 alleles (out of many possible) at 6 different loci (e.g., A, B, C, DP, DQ, DR) results in extremely low chances that all HLA antigens of 2 unrelated individuals are the same.
• Minor Histocompatibility Antigens are minor transplantation antigens
  • Include non-ABO blood group alloantigens and antigens associated with the sex chromosomes.
  • Weaker than MHC antigens. May be targeted by the immune system in late-onset rejection.

Graft Rejection

• A specific immune response to an organ or tissue graft leading to inflammation, damage, and possible graft failure.
• Hyperacute Rejection:
  • A form of allograft or xenograft rejection that begins within minutes to hours after transplantation
  • Characterized by thrombotic occlusion of the graft vessels.
  • Mediated by preformed (pre-existing) cytotoxic antibodies in the host circulation that bind to donor endothelial antigens. Initiates complement system activation.
• Acute Rejection:
  • Involves vascular and parenchymal injury mediated by T cytotoxic cells, macrophages, and antibodies,
  • Occurs days or weeks after transplantation, resulting in skin rashes, diarrhea, and increased risk of infection.
• Chronic Rejection:
  • An allograft rejection characterized by progressive fibrosis of blood vessels in the grafted tissue and loss of normal organ structures over a prolonged period.
• Major Pathologic Feature: Graft arterial occlusion caused by proliferation of intimal smooth muscle, also called graft arteriosclerosis.
• Graft Versus Host Disease (GVHD):
  • Occurs in bone marrow transplant recipients due to the reaction of mature T cells in the marrow graft with alloantigens on host cells.
  • Organs most often affected are skin, liver, and intestines.

Hypersensitivity

• Clinical presentation of acute rejection and GVHD is similar to Type IV hypersensitivity.
  • Hyperacute rejection is a Type II hypersensitivity
  • Chronic rejection can be both Type III and IV hypersensitivity.

Tumor Immunology

• Deals with the relationship between host's immune function and tumor cells.
• Describes the interaction between the cells of the immune system.
• Understanding on how the immune system works against tumor cells is crucial in the management of cancer and the development of new therapies for cancer

Tumor

• Abnormal mass of tissue.
• A result of conversion or transformation of a normally dividing cell into one with uncontrollable growth.
• Can be benign or malignant

Benign vs. Malignant Tumors

Terminology

• Carcinoma: Tumor originating from the skin or epithelial linings of internal organs or glands.
• Sarcoma: Tumors arising from connective tissue (e.g., bone, adipose tissue, cartilage, tendon, muscle).
• Apoptosis: A normal homeostatic mechanism involving biochemical reactions.
  • Leads to:
    • Chromatin condensation.
    • DNA fragmentation.
    • Cell shrinkage.
    • Membrane blebbing.

Tumor Antigens

• Tumor-Specific Antigen:
  • Unique to the tumor of an individual patient or shared by a limited number of patients with the same type of tumor.
  • Not expressed on normal cells.
  • Potential target for anti-tumor immune responses.
• Tumor-Associated Antigen (aka. Tissue-Specific Antigen):
  • Expressed by normal cells as well as tumor cells.

Tumor Specific/Associated Antigens

• Primary cancer associations are shown in parentheses.

Terms continued

• Tumor-Specific Antigen Transplantation Antigen (TSTA):
  • An antigen expressed on experimental animal tumor cells.
  • 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 patients with a specific type of cancer.
• Metastasis:
  • Ability of cells to break away from the original tumor mass and spread through the blood to nearby or distant sites in the body.
• Neoplasia:
  • Continuous multiplication of cells in the absence of a known stimulus.

Clinical Application of Tumor Markers

• Screening
• Diagnosis
• Prognosis
• Monitoring

Categories of Clinically Relevant Tumor Markers

Lab Detection of Tumors

• Gross and Microscopic Morphology
• Tumor Markers by IHC
• Molecular Diagnostics

Etiologies of Cancer

• Mutation in Genes
  • Physical: exposure to ionizing radiation, UV rays
  • Environmental: cigarette smoke and exposure to chemicals (asbestos)
• Infection with Tumorigenic Viruses
  • Examples: HBV, HIV, Human Papilloma viruses
• Expression or Conversion of Proto-oncogenes into Oncogenes
  • 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 an Oncogene.
    • Oncogenes encode proteins that induce cellular transformation.
• Tumor Suppressor Genes inhibit the growth of tumors.

Human Viruses Associated With Cancer

Immunoproliferative Diseases

• Malignant transformation of Hematologic Cells.
  • Cell Properties
  • Genetic Changes
• Types:
  • Leukemia
  • Lymphoma
  • Plasma Cell Dyscrasia

Leukemia

• Cancer that affects the blood-forming tissue.
  • Specifically the bone marrow
• Malignant cells present primarily in bone marrow and peripheral blood.
• Two Groups:
  • Myelogenous: Derived from common myeloid precursor and encompass granulocytic, monocytic, megakaryocytic, and erythrocytic leukemias.
  • Lymphocytic: Originates from mature lymphocytes or their precursors.
• Two Types:
  • Chronic: Slowly progressive and compatible with extended survival.
    • Generally not curable with chemotherapy.
  • Acute: Rapidly progressive and has a higher response rate to therapy.

Acute Lymphocytic Leukemia:

- 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.
- Usually seen in children between 2 to 5 years old (most common type).
- Treatable with a remission rate of 90% and cure rate of 80% in children.
- Four Types:
    - T-cell
    - Mature B-cell
    - CD-10 Expressing Precursor B-cell
    - Precusor B-cell without CD10

Chronic Lymphocytic Leukemia:

- Group of leukemias almost exclusively of B-cell origin. Types:
    - CLL
    - SLL

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 over 20 years old
- Characterized by pancytopenia, splenomegaly, and no lymphadenopathy.
- Malignant cells express B-cell markers CD19, CD20, and CD22.

Lymphoma

• Neoplasm of lymphoid or Ret

• Two Types:

  • Hodgkin Lymphoma
    • Commonly found
    • Curable
    • Occurs in the young and the elderly
    • Found in the Peripheral LN (lymph node), lungs, liver, and BM (bone marrow)
  • Non-Hodgkin Lymphoma
    • 2/3 of cases are over 60 yrs old
    • More often in men
    • Immunosuppresion with the greatest risk

• Condition associated with increased risk of NHL (Non-Hodgkins Lymphoma)

  • Ceratin autoimmune diseases
  • Congenital Immunodeficiency Disorders
  • Organ Transplantation
  • Exposure to Infectious Agents

Plasma Cell Dyscrasias

• Dyscrasia refers to the abnormal or disordered state of the body or body part.
• A group of conditions characterized by the abnormal proliferation of plasma cells, the antibody-producing cells.
  • Multiple Myeloma
  • Waldenstrom Macroglobulinemia
  • Smoldering MM
  • MGUS

Myeloma Protein

• An 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.
  • Characterized by excess plasma cells in the bone marrow.
    • Also known as plasma cell myeloma.
• Overproduction of the monoclonal IgG.
  • 20% of myeloma cells express CD20.

Multiple Myeloma

• Clinical Manifestations:
  • Hematologic
  • Skeletal
  • Immunologic. Defects:
  • Kidney Injury
  • Cardiomyopathy
  • Peripheral Neuropathy
  • 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
• Clinical signs:
  • Weakness
  • Fatigue
  • Anemia
  • Bleeding
  • Hyperviscosity
• Hyperviscosity
  • Can develop when the level of M protein in the plasma is high.
  • Seen in IgM producing tumors.