Comprehensive Study Guide on Transplantation: HLA, Solid Organs, and Hematopoietic Stem Cells

Introduction to Clinical Transplantation

• Definition and Scope of Transplantation: Currently, a wide variety of human tissues and organs are routinely transplanted to treat various conditions. These include:

  • Bone marrow.
  • Peripheral stem cells.
  • Bone matrix.
  • Skin.
  • Kidneys.
  • Liver.
  • Cardiac valves.
  • Heart.
  • Pancreas.
  • Corneas.
  • Lungs.

• The Specific Challenges of Transplantation:

  • Genetic Variation: The inherent genetic differences between the donor and the recipient.
  • Immune Recognition: The recipient’s immune system recognizes these genetic differences as foreign, leading to the immune-mediated rejection of the transplanted organ.

Histocompatibility Antigens (HLA)

• Major Histocompatibility Complex (MHC):

  • The MHC serves as the fundamental basis for biological compatibility between individuals.
  • Genetic Localization: The genes for the MHC are located on Chromosome $6$ at band $21$ ($6p21$).

• Human Leukocyte Antigens (HLA):

  • Function: HLA molecules are responsible for T cell discrimination of "self" versus "non-self."
  • Process: They present peptides to T cells for recognition. If recognized as foreign, the T cells initiate the elimination of the carrier cell.
  • Role in Rejection: Recognition of MHC class molecules as "foreign" by the recipient’s immune system results in graft rejection.
  • Graft-Versus-Host Disease (GVHD): This occurs when immune cells from the donor target the "foreign" cells of the recipient.

• Genomic Structure of the HLA Region (Complex Mapping):

  • The region is measured in kbases (ranging from $0$ to over $3600$).
  • Class II Region: Includes genes such as $DP$ ($A2$, $B2$, $B1$, $A1$), $DM$ ($AB$), $TAP1$, $TAP2$, $DQ$ ($A2$, $B2$, $B3$, $A1$, $B1$), and $DR$ ($B2$, $B3$, $B1$, $B5$, $A$).
  • Class III Region: Contains genes for Complement (Factor $B$, $C4B$, $C4A$, $C2$), $HSP-70$, $TNF-\alpha$, $LTB$, and $LT$.
  • Class I Region: Features $HLA-B$, $HLA-C$, $HLA-E$, $HLA-J$, $HLA-A$, $HLA-H$, $HLA-G$, and $HLA-F$.

HLA Nomenclature and Alleles

• Naming Conventions: HLA antigens are assigned a unique name consisting of $4$, $6$, or $8$ letters/digits. The structure defines the biology:

  • First $2$ digits: Represents the allotype.
  • $3$rd and $4$th digits: Represents the subtypes.
  • Additional digits: Indicate the specific allele sequence or nearest relative.

• Examples of Nomenclature (New vs. Shorthand):

  • Class I:
    • $\text{HLA-A*0101}$ is frequently referred to as $\text{HLA-A1}$.
    • $\text{HLA-B*0801}$ is frequently referred to as $\text{HLA-B8}$.
  • Class II:
    • $\text{HLA-DRB1*0101}$ is frequently referred to as $\text{HLA-DR1}$.
    • $\text{HLA-DRB1*0301}$ is frequently referred to as $\text{HLA-DR3}$.

• MHC Class Comparisons:

  • MHC Class I: Encompasses the $A$, $B$, and $C$ regions.
  • MHC Class II: Focused on the $D$ region, specifically $DR$, $DC$ ($DQ$), and $DP$ ($SB$).

The Transplantation Process and Registries

• HLA Matching:

  • A perfect match is typically described as an $8$ of $8$ match or a $10$ of $10$ match (including specific alleles for $A$, $B$, $C$, $DRB1$, and $DQ$).
  • A mismatch is represented by scores such as $7$ of $8$ or $9$ of $10$.

• Transplant Registries (Example Workflow):

  • A patient in renal failure needs a kidney. They are typed at the $A$, $B$, and $DR$ loci (e.g., $\text{A5 B13 DR1}$).
  • The patient is added to a register with many others, all with diverse HLA types (e.g., $\text{A2 B7 DR2}$, $\text{A3 B11 DR1}$, $\text{A1 B8 DR3}$, etc.).

• Organ Donation Step-by-Step:

  • 1. A potential donor is HLA typed.
  • 2. Kidneys are sent to hospitals where a registered patient provides a good HLA match.
  • 3. A Crossmatch is performed: Donor $B$ cells are mixed with recipient serum.
  • 4. Outcomes:
    • If preformed antibodies in the recipient serum bind to donor cells, the transplant cannot take place.
    • If the recipient has no antibodies against donor cells, the transplant can proceed.

Transplantation Terminology

General Statistics and Lab Techniques

• Survival and Transplant Volume (Unadjusted Numbers):

  • Deceased Kidney Donor: $17,760$ (at $1$ year); $34,901$ ($3$ years); $49,989$ ($5$ years); $84,554$ ($10$ years).
  • Living Kidney Donor: $10,773$ (at $1$ year); $22,367$ ($3$ years); $34,056$ ($5$ years); $58,235$ ($10$ years).
  • Deceased Liver Donor: $10,369$ (at $1$ year); $20,891$ ($3$ years); $30,505$ ($5$ years); $50,506$ ($10$ years).
  • Living Liver Donor: $464$ (at $1$ year); $1054$ ($3$ years); $1679$ ($5$ years); $3264$ ($10$ years).

• Advanced Laboratory Techniques:

  • Flow Cytometry.
  • Molecular Techniques.
  • Bead Technology.
  • Donor-Specific Antibody Tests.

Hematopoietic Stem Cell Transplantation (HSCT)

• Diseases Treatable by Stem Cell Transplantation:

  • Leukemias: Acute lymphoblastic (ALL), Acute myelogenous (AML), Chronic myelogenous (CML), Chronic lymphocytic (CLL).
  • Myelodysplastic Syndromes: Refractory anemias, Chronic myelomonocytic leukemia.
  • Stem Cell Disorders: Aplastic anemia, Fanconi's anemia, Paroxysmal nocturnal hemoglobinuria.
  • Myeloproliferative Disorders: Primary myelofibrosis, Polycythemia vera.
  • Lymphoproliferative Disorders: Non-Hodgkin lymphoma, Hodgkin disease.
  • Phagocyte Disorders: Chédiak-Higashi syndrome, Chronic granulomatous disease.
  • Immunodeficiencies: Severe combined immunodeficiency (SCID).
  • Platelet/Erythrocyte Abnormalities: Congenital thrombocytopenia, Beta-thalassemia major, Pure red cell aplasia, Sickle cell disease.
  • Plasma Cell Disorders: Multiple myeloma, Plasma cell leukemia, Waldenström's macroglobulinemia.
  • Other Malignancies: Breast cancer, Ewing's sarcoma, Neuroblastoma, Renal cell carcinoma.
  • Liposomal Storage Diseases: Hurler's syndrome, Gaucher's disease, Niemann-Pick disease.

• Sources of Stem Cells:

  • Bone marrow.
  • Peripheral blood stem cells (PBSC).
  • Umbilical cord blood.
  • Types include Allogeneic, Syngeneic, and Autologous.

Graft Rejection Mechanisms

• Immunogenicity Hierarchy (Most to Least Immunogenic):

  • 1. Bone marrow (Highest).
  • 2. Skin.
  • 3. Islets of Langerhans.
  • 4. Heart.
  • 5. Kidney.
  • 6. Liver.
  • 7. Bone.
  • 8. Xenogeneic valve replacements.
  • 9. Cornea (Lowest).

• Categories of Graft Rejection:

• Key Features of Rejection:
  • Memory and Specificity: Rejection displays key features of adaptive immunity.
  • Role of T Cells: Primarily regulated by host T cells interacting with graft antigens.
  • Antibody Effects: Can cause rapid rejection but are usually less significant than cell-mediated immunity.

Immunosuppression Treatment

• Drug Regimens and Mechanisms:
  • Corticosteroids: Reduce inflammation by inhibiting macrophage cytokine secretion.
  • Cyclosporine / Tacrolimus (FK506): Block T-cell cytokine production by inhibiting calcineurin phosphatase and blocking the NFAT transcription factor.
  • Mycophenolate mofetil: Inhibits guanine nucleotide synthesis, blocking lymphocyte proliferation.
  • Rapamycin: Blocks lymphocyte proliferation by inhibiting $IL-2$ signaling.
  • Anti-IL-2 receptor (CD25) antibody: Inhibits T-cell proliferation by blocking $IL-2$ binding; opsonizes activated T cells.
  • CTLA4-lg (belatacept): Blocks $B7$ costimulator binding to T-cell $CD28$.
  • Antithymocyte globulin: Depletes T cells via phagocytosis or complement-mediated lysis (used for acute rejection).
  • Anti-CD52 (alemtuzumab): Depletes lymphocytes via complement-mediated lysis.

Transplantation Complications and Xenotransplantation

• Post-Organ Complications: Infectious disease, cancer, osteoporosis, diabetes, hypertension, and hypercholesterolemia.

  • Post-Stem Cell Complications: Infertility, organ damage, and death.

• Graft-Versus-Host Disease (GVHD):

  • Etiology: Immunocompetent donor lymphocytes recognize the host antigens as foreign. Because the host is immunosuppressed, they cannot destroy these donor cells, leading to injury.
  • Requirements: Source of immunocompetent lymphocytes (blood, marrow, organ), HLA differences, and host inability to reject donor cells.
  • Signs/Symptoms: Inflammatory response occurring within $3-30$ days. Infiltration of intestine, skin, and liver. Jaundice, fever, anemia, weight loss, and a maculopapular rash on palms and soles.
  • Chronic GVHD: Persistence beyond $100$ days; resembles collagen vascular disease.
  • Prevention: Irradiation of blood products or bone marrow; depletion of specific cell types.

• Milestones in Xenotransplantation:

  • 1963-1964: Chimpanzee to human renal transplants.
  • 1964: Pig heart valve transplant.
  • 1968: Sheep heart transplant.
  • 1984: "Baby Fae" received a baboon heart.
  • 1992: Baboon to human liver transplant.
  • 1994: Pig pancreatic islets to insulin-dependent patients.
  • 1995: Fetal pig neuronal cells for Parkinson's disease.
  • 1996: Baboon bone marrow transplanted to an AIDS patient.