Transplantation Immunology

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Transplantation Immunology

  • Transplantation is the process of taking cells, tissues, or organs from one individual and transferring them to the same or different individual

    • Blood transfusions are a common form of transplantation practiced in veterinary medicine

Allograft Rejection

  • Host vs. graft disease

    • Autologous and syngeneic grafts are accepted by the Recipient’s (host) immune system because the graft (Donor) antigens are identical to recipient antigens

    • Graft rejection occurs when graft antigens are different than Recipient antigens and, thus, recognized as foreign

  • The genetics of graft rejection (an experiment)

  • Autologous and syngeneic grafts are readily accepted

  • Allografts between mouse strains are rejected in 7-10 days

  • Graft from an inbred parental strain to the F1 hybrid progeny is accepted

  • Graft from the F1 progeny to the inbred parental strain is readily rejected

  • If Recipient has never been exposed to Donor antigens before, allograft rejection typically requires 7 – 10 days

  • Once sensitized to Donor antigens by the first graft, the Recipient will reject a second (and all subsequent grafts from same Donor) in about 3 days – second set rejection

    • This reaction is due to rapid response by memory lymphocytes

  • If lymphocytes are isolated from a Recipient strain B mouse that has already rejected a graft from a strain A mouse, adoptive transfer of those cells to a naïve strain B mouse will cause that mouse to reject a graft from strain A in about 3 days

  • Recipient lymphocytes are responsible for allograft rejection

Mechanisms of Alloantigen Recognition

Which Donor antigens (alloantigens) do Recipient lymphocytes recognize and how are these alloreactive Recipient lymphocytes activated?

  • Classes of alloantigens

    • Major histocompatibility (MHC) antigens

      • Donor MHC molecules in the graft play a role completely unrelated to antigen presentation

      • Most powerful alloantigens involved in activation of Recipient lymphocytes

      • MHC molecules were initially identified this way

    • Minor histocompatibility antigens

  • Direct presentation

    • Donor APCs from the graft traffic to regional lymph nodes and present antigen to Recipient T cells

    • Donor MHC molecules are intact and interact directly with Recipient TCRs

      • Up to 2% of Recipient T cells express TCRs that interact directly with antigenic determinants formed by either Donor MHC molecules or Donor MHC – peptide complexes

      • Even when the antigen determinants are formed only by the Donor MHC molecules, MHC-bound peptide is required for stable expression of the Donor MHC molecules

      • TCR : MHC interaction provides the first signal of Recipient T cell activation

      • The second signal for Recipient T cell activation is provided by costimulatory molecules (B7-1) expressed on the surface of Donor APCs

    • Direct presentation evokes the most powerful T cell response

      • During normal antigen presentation (i.e. viral infection) only a small fraction (~1%) of MHC molecules on an APC are loaded with viral peptide while the rest are loaded with self antigens

        • Thus, only a small number of host lymphocytes are specific for the MHC – viral peptide complex

        • Takes 7-10 days for this small population of lymphocytes to clear the infection

      • In contrast, up to 2% of Recipient T lymphocytes can directly interact with the thousands of copies of Donor MHC molecules present on graft APCs

      • The combination of more Recipient lymphocytes capable of responding to Donor MHC molecules and the abundance of MHC molecules on the surface of Donor APCs yields an extremely powerful immune response

  • Indirect presentation

    • Recipient APCs travel to graft, collect Donor antigens, and travel back to regional lymph node for T cell presentation

      • Donor antigen (either Major or Minor histocompatibility molecules) are processed by Recipient dendritic cells and presented to Recipient T cells

      • Only a small fraction (~1%) of Recipient MHC molecules on a given APC are loaded with Donor antigens

      • Only a small number of Donor antigen-specific lymphocytes (~.0001?) can interact with this MHC – Donor peptide complex

      • Thus, it takes 7-10 days for this small population of lymphocytes to expand and attack the graft

Mixed Lymphocyte Response (MLR)

  • Excellent way to demonstrate the response of alloreactive Recipient T cells to Donor MHC molecules

  • Peripheral blood mononuclear cells (PBMCs) are collected from unrelated (i.e. have different MHC molecules) Donors X and Y

  • Donor Y PBMCs are rendered unable to proliferate via sub lethal radiation or incubation with mitomycin C

  • Donor X PBMCs are added to inactivated Donor Y PBMCs in tissue culture

  • Up to 2% of Donor X CD4+ and CD8+ cells are capable of recognizing MHC molecules on Donor Y APCs

  • Donor X CD4+ and CD8+ cells proliferate vigorously and produce cytokines

  • The robustness of the lymphocyte proliferation response is proportional to the degree of MHC molecule difference between Donors X and Y

  • This crude test can also be used to determine if two individuals have exactly the same MHC molecules (i.e. PBMCs collected from monozygotic twins will not proliferate in an MLR)

Effector Mechanisms of Graft Rejection

  • Graft rejection is classified on the basis of how long it takes for the graft to be rejected

  • Graft blood vessels (which are surgically attached to the Recipient circulatory system) are the first structures to be exposed to the Recipient immune system and are, thus, the initial location of graft rejection

  • Hyperacute rejection

    • Characterized by thrombotic occlusion of graft vasculature within minutes to hours after Recipient blood vessels are linked to the graft blood vessels

    • Antibodies in the Recipient that recognize Donor antigens are alloantibodies

      • Before tissue cross-matching became routine, graft rejection was mediated by preexisting “natural antibodies” of the IgM class that bound to graft vascular antigens. These antibodies arose in response to carbohydrate antigens expressed by gut microflora and recognized foreign blood groups. However, hyperacute rejection die to blood group incompatibility has largely been eliminated by ensuring the Donor and Recipient have the same blood type

      • Today, hyperacute rejection is mediated by IgG antibodies specific to donor antigen from previous exposure (i.e. previous transplantation, blood transfusion, multiple pregnancies)

    • Mechanism of action

      • Recipient alloantibodies bind alloantigens expressed on endothelium of Donor vasculature

      • Antibody deposition on vasculature has numerous effects that lead to pathological thrombosis

        • Complement activation – endothelial damage, basement membrane denudation

        • Secretion of Von Willebrand Factor

        • Activation of the clotting cascade, platelet accumulation (thrombotic occlusion)

        • Recruitment of neutrophils to Donor vasculature

    • How to prevent hyperacute rejection?

      • Check for pre-existing anti-donor antibodies via crossmatching

        • Major crossmatch – Donor erythrocytes incubated with recipient serum

        • Minor crossmatch – Donor serum, recipient erythrocytes

  • Acute rejection

    • Characyerized by vascular and parenchymal injury mediated by T cells and antibodies that usually begins a week after transplantation

    • Mechanism of action

      • Recipient alloreactive T cells and/or antibodies develop after transplantation

      • Alloreactive T cells recognize Donor alloantigens (particularly MHC molecules) expressed by the endothelium of the graft blood vessels and parenchymal cells

      • Alloreactive CD8+ cells can directly kill the graft cells

      • Alloreactive CD4+ and CD8+ cells can become activated and produce cytokines

      • Microscopically, this appears as non-suppurative endothelitis (inflammation of the blood vessel wall mediated by mononuclear cells) and is a hallmark of graft rejection

      • Alloantibodies bind to graft endothelium, activate complement, resulting in transmural vascular necrosis (i.e. entire vessel wall thickness) and neutrophil recruitment

  • Chronic rejection

    • Because the use of immunosuppressive drugs and tissue-typing methods to obtain optimum match of Donor and Recipient tissue increases survival of allografts, chronic rejection has become the most common forms of graft rejection

    • Characterized by arterial occlusion as a result of intimal smooth muscle proliferation and/or fibrosis that occurs over time, months to years after transplantation

    • Mechanism of action

      • Recipient alloreactive T lymphocytes develop after transplantation

      • Intimal smooth muscle cell proliferation

        • Alloreactive T cells infiltrate the graft

        • T cells can produce cytokines that directly stimulate smooth muscle proliferation

        • T cells can induce monocytes or macrophages to secrete smooth muscle growth factors

      • Fibrosis

        • Alloreactive T cells can infiltrate the graft and promote fibroblast proliferation

        • May occur in response to transmural vascular necrosis following acute rejection

Prevention and Treatment of Allograft Rejection

  • Match Donor and Recipient MHC molecules as closely as possible

    • Because MHC molecules are the most powerful alloantigens associated with graft rejection, precise matching of Donor and Recipient MHC molecules reduces the incidence and severity of graft rejection

  • Inhibit T cell activation by blocking co-stimulation

    • CTLA4-Ig – binds B7-1 on APCs and prevents T cell co-stimulation via CD28

  • Immunosuppressive drugs

    • Drugs that Inhibit T lymphocyte proliferation

      • Cyclosporine

      • FK506

      • RapamycinAnti-CD25

      • Azathioprine

      • Mycophenolate mofetil

    • Drugs that kill T lymphocytes

      • Anti-CD3 (OKT3)

    • Immunosuppressive drugs that cause non-specific immunosuppression

      • Corticosteroids – inhibit secretion of cytokines by many cell types

Bone Marrow Transplantation

  • Reasons for bone marrow transplantation

    • Treat hematologic malignancies

    • Treat solid tumors (experimental)

    • Correct inherited deficiencies of enzymes or proteins

  • Bone marrow transplant protocol

    • Recipient is “prepared” to receive graft via high dose radiation and chemotherapy

      • Kills Recipient bone marrow and leukocytes populating lymphoid organs

      • Prevents Recipient from rejecting bone marrow graft

        • Even a few residual Recipient leukocytes (particularly NK cells) can promote rejection

      • Provides “space” in the bone marrow and lymphoid organs for the grafted cells to grow

    • Harvest Donor transplant cells

      • Whole bone marrow was traditionally used, though this led to a high incidence of graft vs. host disease because marrow contained large populations of mature, alloreactive lymphocytes

      • Now, purified CD34+ bone marrow stem cells are used

        • Monoclonal antibodies are used in this process to deplete Donor marrow of mature alloreactive lymphocytes, decreasing the incidence of graft vs. host disease

      • New technique using umbilical cord CD34+ stem cells

        • Cells are less differentiated and, thus, less likely to contain alloreactive lymphocytes

      • New technique of treating Donor with bone marrow-stimulating cytokines (i.e. GMCSF) to stimulate CD34+ stem cell production and release into peripheral blood

        • Peripheral blood is collected, then sorted for CD34+ cells (avoid general anesthesia, less painful procedure)

    • CD34+ stem cells differentiate into mature RBCs, granulocytes, megakaryocytes, NK, T, and B cells

    • Treat Recipient with immunosuppressive drugs to prevent rejection

      • Recipient is treated for an extended period of time and gradually weaned off

      • Danger of long-term immunosuppression is susceptibility to infection

    • Support Recipient until grafted marrow starts repopulating blood with new RBCs, WBCs, and platelets

  • Graft versus host disease

    • Occurs when alloreactive Donor T cells and NK cells of a graft attack Recipient tissues

    • In both forms, CD8+ T cells and NK cells may be responsible for the observed epithelial injury

      • Acute form

        • Results in major organ necrosis and dysfunction (liver, kidneys, GI tract, skin, lungs)

      • Chronic form

        • Results in organ atrophy and/or fibrosis

    • Methods to minimize graft versus host disease

      • Carefully match Donor and Recipient at all MHC loci

      • Deplete Donor marrow of mature lymphocytes and NK cells

      • Treat Recipient with immunosuppressive drugs

    • Beneficial effects of graft versus host disease

      • In leukemia patients, a low level of graft versus host disease is shown to be beneficial because grafted T lymphocytes kill any residual leukemia cells in the Recipient

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