9 Principles of Pharmacology - Immunosuppression for Solid Organ and Bone Marrow Transplantation
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Course
Pharmacology
Institution
Pharmacology
The object of the course is to teach students an approach to the study of pharmacologic agents. It is not intended to be a review of the pharmacopoeia. The focus is on the basic principles of biophysics, biochemistry, and physiology as to the mechanisms of drug action, biodistribution and metabolis...
Harvard-MIT Division of Health Sciences and Technology
HST.151: Principles of Pharmocology
Instructor: Prof. Thomas Spitzer
Spitzer/HST-151 1
Immunosuppression for Solid Organ and Bone Marrow Transplantation
Thomas R Spitzer, MD
Overview
The success of solid organ and bone marrow transplantation (BMT) has correlated with
improvements in selective immunosuppression. Immunosuppression decreases both the
incidence of acute and chronic organ graft and bone marrow rejection, and a potentially
life threatening complication of BMT known as graft-vs-host disease (GVHD). Selective
immunosuppression targets specific pathways of immune signaling and activation, and
minimizes the incidence of deleterious side effects.
History
• 1954: First successful human kidney transplant
• 1960s: Introduction of effective immunosuppressive drugs. Steroids, ATG,
azathioprine
• 1968: Successful bone marrow transplants for congenital immunodeficiency
syndromes
• 1970s: Cyclosporine introduced
• 1980s: OKT3, tacrolimus, mycophenolate mofetil introduced
• In 1988 1 year renal cadaver graft survival was 76% and 1 year renal living donor
graft survival was 89%
▫ By 1995, graft survival rates improved to 87% and 93% respectively
• 1980s: The addition of cyclosporine to GVHD prophylaxis regimens halved the
incidence of severe disease and improved survival post -transplant
• 1990s: Leflunomide, TNF antagonists, and selective mAbs introduced; additional
mAb therapies expected in future
Balancing Benefits and Risks of Immunosuppression
Benefits: Immunosuppression decreases risks of both acute and chronic organ graft and
bone marrow rejection, and GVHD
Risks: Immunosuppression poses risk of several types of side effects to the patient:
• Acute effects: gastrointestinal upset
• Opportunistic infection because patient is immunocompromised: CMV, Candida,
Pneumocystis carinii, etc.
• Malignancies (lymphomas, skin cancer, etc.)
• Toxicities specific to particular immunosuppressive agent: steroids, etc.
, Spitzer/HST-151 2
Types of Organ Graft Rejection
• Hyperacute: Occurs within minutes after transplant. Mediated by preformed anti-
donor antibodies in recipient. Involves small vessel thrombosis and graft infarction.
• Acute: Occurs weeks after transplant. Delayed-type hypersensitivity / Cell mediated
response of cytotoxic T lymphocytes reacting against the foreign MHC molecules of
the graft. Histologically characterized by mononuclear infiltrate, hemorrhage, and
edema in graft. Reversible with immunosuppressive therapy.
• Chronic: Occurs months to years post transplant. Results from antibody mediated
vascular damage (fibrinoid necrosis) and is irreversible. Vascular damage results in
vascular cell wall proliferation which may occlude vessel lumen resulting in graft
ischemia and fibrosis. Can progress insidiously despite increased immunosuppressive
therapy.
Graft Rejection and GVHD Following Bone Marrow Transplantation
• Graft rejection occurs uncommonly (<1%) after conventional myeloablative bone
marrow/stem cell transplantation, with increased incidence (1-15%) after HLA-
mismatched BMT/cord blood transplantation.
• The rate of graft rejection is higher after nonmyeloablative preparative therapy for
BMT
• Acute GVHD, which is usually evident before day 100 post-transplant, occurs in 1/3
of HLA matched transplants and 2/3 of HLA-mismatched transplants.
• Chronic GVHD (>day 100) occurs in approximately ½ of transplants
• Acute GVHD affects predominantly skin, the GI tract, and liver. Tissue injury
involves effector cells (initiated by T-cells), particularly of the TH1 subset, and
cytokines (e.g. TNF-alpha, interferon-gamma, and interleukin-1).
• Chronic GVHD may affect almost any organ/tissue and often mimics a collagen
vascular disease in its clinical presentation.
Molecular Basis of Immune Response and Immunosuppression
The immune response involves both humoral and cellular responses:
Humoral: The humoral response involves recognition of foreign antigens which causes
the differentiation of B-cells into memory cells and plasma cells. Plasma cells secrete
antibodies into circulation.
Cellular: Macrophages ingest and present antigen via the major histocompatibility
(MHC) II molecule. The macrophage is a type of antigen presenting cell which binds to
CD4 T lymphocytes cells via the MHC II – T cell receptor (TCR) interaction. CD3 is a
necessary accessory molecule to the MHC II – TCR interaction. The interaction induces
proliferation of the CD4 T-cell (see diagram page 4), and release of IL-2, which
promotes activation of cytotoxic CD8 T-cells. CD8 T cells bind to MHC I molecules.
When CD8 cells recognize an antigen presented on an MHC I molecule (which indicates
the presenting cell is foreign, or, for example, a tumor cell or virally infected cell) the
CD8 cell induces the death of the target.
In the context of an MHC mismatched organ or bone marrow transplant, the MHC
molecules of the cells of the organ (or bone marrow) graft are recognized by the host
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