DOC PREVIEW
MIT HST 151 - Immunosuppression for Solid Organ and Bone Marrow Transplantation

This preview shows page 1-2 out of 7 pages.

Save
View full document
View full document
Premium Document
Do you want full access? Go Premium and unlock all 7 pages.
Access to all documents
Download any document
Ad free experience
View full document
Premium Document
Do you want full access? Go Premium and unlock all 7 pages.
Access to all documents
Download any document
Ad free experience
Premium Document
Do you want full access? Go Premium and unlock all 7 pages.
Access to all documents
Download any document
Ad free experience

Unformatted text preview:

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 hostSpitzer/HST-151 3 TCR not as self-MHC molecules, but rather in the same manner as a self-MHC plus the foreign peptide it is presenting. The immunologic response to the foreign MHC molecules is a major cause of most graft rejection. Conversely the donor immune system may recognize disparate MHC antigens in the host and initiate an immunologic response in the form of GVHD. MHC molecules are divided into class I and class II antigens; inheritance involves multiple alleles, and all loci are found on chromosome 6. Class I antigens include HLA-A, HLA-B, and HLA-C alleles . Class II antigens include HLA-DR, HLA-DQ, and HLA-DP alleles. Minimization of the antigenic differences between donor and recipient, by matching their MHC alleles, has decreased rejection and GVHD and improved graft survival. Identical twins have identical MHC genes (6/6 loci), siblings have half similarity (3/6), and the match of unrelated persons must be determined by tissue typing. As most bone marrow/stem cell transplants are from HLA matched (or only minor mismatched) related or unrelated donors, minor histocompatibility antigens play a large role in eliciting an immune response (GVHD). Polymorphisms of minor histompatibility antigens have been identified as risk factors for GVHD in the HLA-matched setting. Types of Immunosuppressive Agents and Sites of Action The schematic on page 4 shows the


View Full Document

MIT HST 151 - Immunosuppression for Solid Organ and Bone Marrow Transplantation

Download Immunosuppression for Solid Organ and Bone Marrow Transplantation
Our administrator received your request to download this document. We will send you the file to your email shortly.
Loading Unlocking...
Login

Join to view Immunosuppression for Solid Organ and Bone Marrow Transplantation and access 3M+ class-specific study document.

or
We will never post anything without your permission.
Don't have an account?
Sign Up

Join to view Immunosuppression for Solid Organ and Bone Marrow Transplantation 2 2 and access 3M+ class-specific study document.

or

By creating an account you agree to our Privacy Policy and Terms Of Use

Already a member?