Current Development and the Importance of the Major Histocompatibility Complex in Transplantation - Research Paper Example

Introduction The Major Histocompatibility Complex (MHC) plays an important role in transplant rejection. However, the long-term survival of thetransplanted organs is always in jeopardy because of the immune system. Although treatment with immunosuppressive agents prevents rejection, it however, makes the transplant recipients more susceptible to opportunistic infections and tumour development. The purpose of this study was to know more about the role of MHC, B and T cell receptors, cytokines and the current development in the field of transplantation, and the alternative approaches being tried for inducing immunological tolerance. Major Histocompatibility Complex (MHC) The Major Histocompatibility Complex (MHC) comprises of a set of molecules present on cell surfaces. This complex is responsible for lymphocyte recognition and antigen presentation. By the recognition of “self” and “non-self”, MHC molecules control the immune response, and are therefore, involved in transplantation rejection. Two classes of the MHC are recognized, Class I and Class II MHC molecules, which belong to the Immunoglobulin Supergene Family. T-cell receptors, immunoglobulins, CD4, CD8, and others also belong to this family. Class I and class II molecules show specifity in their binding. MHC class I molecules specifically bind CD8 molecules, which are expressed on cytotoxic TC lymphocytes, while MHC class II molecules specifically bind CD4 molecules, which are expressed on helper TH lymphocytes (Sears DW, Christensen SR, 1997.) Genes, which are located on human chromosome 6 encodes for the MHC. The BCA region encodes for Class I molecules, while the D region encodes for class II molecules. The region present in between BCA and D region on chromosome 6 encodes class III molecules, including some complement components (Major Histocompatibility, n.d.) Extensive research has clarified the understanding of the cis-elements and transcription factors that regulate the expression of Class II MHC genes. The discovery of CIITA, a non- DNA binding activator of transcription that is a master control gene for class II gene expression is a crucial discovery. (Radosevich M, Ono SJ, 2003) Both B cells and T cells have the ability to recognize and respond to antigens with the help of special receptor molecules, which are present on their surface. In the B cell, this receptor is an antibody-like receptor, which allows the B cell to interact with an antigen in the blood or other body fluids. In contrast, the T cell receptor is more complex (Immune System Series, n.d.) T-Cell Receptor (TCR) Molecules TCR is composed of two, disulfide-linked polypeptide chains, alpha and beta, each having separate, constant and variable domains. The variable domain is made of three hypervariable regions, which are responsible for antigen recognition. Although the TCR allows T-cells to recognize their particular antigenic moiety, the T-cells need help to recognize the antigen. After the antigenic determinant is presented by an MHC molecule, the signal is passed to the CD3 molecule and then to the T-cell, which causes T-cell activation and lymphokine release. Therefore, antigen recognition by T cells is said to be “MHC-restricted”, since the TCR requires interactions with MHC. In addition, interactions between the CD4 molecule (present on helper T-cells) and class II MHC or the CD8 molecule (present on cytotoxic T-cells) and class I MHC stabilize and fulfil the antigen recognition process. The helper T-cells are thus able to respond to exogenous antigens with subsequent B-cell activation and antibody production or cytotoxic T-cells respond to endogenous antigens with target cell destruction (Major Histocompatibility, n.d.) The T cell response to antigen has a great degree of both sensitivity and specificity, with a cell responding to 1-10 peptide-MHC complexes and sensitivity to single amino acid substitutions (George AJ, Stark J, Chan C, 2005) B-cell Antigen Receptor The B-cell antigen receptor (BCR) is made of membrane Igs (mIgs), a heterodimer of Ig (CD79a) and Ig (CD79b) transmembrane proteins. These proteins are encoded by the mb-1 and B29 genes, respectively (Payelle-Brogard B, Magnac C et al., 1999.) Cytokines Cytokines are small, secreted proteins, which are produced de novo in response to an immune stimulus. They mediate and regulate immunity, inflammation, and haematopoiesis. By binding to specific membrane receptors, cytokines signal the cell via second messengers (often tyrosine kinases), and alters the cells behaviour (gene expression). The effects include increase or decrease in membrane protein expression (including cytokine receptors), proliferation, and secretion of effector molecules. (Decker JM, 2003.) The proliferation and differentiation of immune cells is stimulated by the largest group of cytokines, which includes: 1. Interleukin 1 (IL-1), which activates T cells. 2. IL-2, which stimulates proliferation of antigen-activated T and B cells. 3. IL-4, IL-5, and IL-6, which stimulate proliferation and differentiation of B cells. 4. Interferon gamma (IFNg), which activates macrophages. 5. IL-3, IL-7 and Granulocyte Monocyte Colony-Stimulating Factor (GM-CSF), which stimulate haematopoiesis. The other groups of cytokines include interferons and chemokines (Decker JM, 2003.) Cytokine Receptors Cytokines are able to act on their target cells by binding specific membrane receptors. Based on their structure and activities, the receptors and their corresponding cytokines have been divided into several families like hematopoietin family receptors, interferon family receptors, tumour necrosis factor family receptors, and chemokine family receptors. (Decker JM, 2003.) Cytokine receptor structure and signal transduction The extracellular domains of the cytokine receptors form tertiary structures, share a similar genomic organization, and have approximately 20% amino acid identity (Bazan 1990, Cosman et al 1990). However, at present, there is no information on the three-dimensional structure of the cytoplasmic region of cytokine receptors. (Watowich SS et al., 1996.) The membrane-proximal portion of the cytoplasmic tail of cytokine receptors is sufficient in most cases for signaling and stimulation of cell proliferation. However, it is not clear which signaling pathways are activated and how they control cell division. (Watowich SS et al.,) MHC in transplantation The past four decades have seen a lot of success in organ transplantation. However, the immune system is a significant barrier as far as the long-term survival of the transplanted organs is concerned. Although treatment with immunosuppressive agents is required to prevent rejection of organ grafts, most of the current immunosuppressive agents are non-specific and make the transplant recipients more susceptible to opportunistic infections and tumour development. (Wong W, Wood KJ, 2004.) By achieving donor specific tolerance the lifelong treatment with immunosuppressive agents can be eliminated, and thereby, avoiding the associated side effects. In experimental models, the pretransplant exposure to donor MHC antigens has been successful in inducing tolerance. Recently, in humans, the administration of donor bone marrow, and pretransplant blood transfusion have been tried to prolong graft survival (Wong W, Wood KJ, 2004.) The use of gene therapy (gene transfer of donor MHC genes to recipient derived cells) may allow the use of fully allogeneic donor bone marrow without the risk of graft-versus-host-disease (GVHD) (Wong W, Wood KJ, 2004.) Although the matching of donor/recipient MHC class II allows survival of experimental allografts without permanent immunosuppression, it is not applicable clinically because of the extensive polymorphism of this locus. In one study (Sonntag KC, Emery DW, et al, 2001), involving a preclinical animal model, a gene therapy approach was tested to determine whether expression of allogeneic class II transgenes (Tgs) in recipient bone marrow cells would allow survival of subsequent Tg-matched renal allografts. The process involved somatic matching between donor kidney class II and the recipient Tgs, along with a short treatment of cyclosporine A. This prolonged graft survival with DR and promoted tolerance with DQ. This tolerance induction was attributed to Class II Tg expression in the lymphoid lineage and the graft. This study, thus demonstrated the potential of MHC class II gene transfer to allow tolerance to solid organ allografts. Currently, the alternative approaches being explored in clinical transplantation for the induction of immunological tolerance include total lymphoid irradiation (TLI) and donor bone marrow transfusion combined with anti-lymphocyte globulin (ALG) post-transplantation. (Wood KJ, 1991.) Woodley SL, Gurley KE, et al, 1993, studied whether post-transplant anti-T cell monoclonal or polyclonal antibody therapy could allow post-transplant total lymphoid irradiation (TLI) to induce tolerance. A Lewis rat was used in the study and the experiments were conducted in a high responder strain combination of an ACI cardiac allograft into the rat. By a combination of anti-pan T cell antibody (anti-CD3) and TLI, it was possible to induce tolerance and all grafts survived more than hundred days. The researchers concluded that in the posttransplant period, monoclonal or polyclonal anti-pan T cell antibodies, TLI, and a donor blood cell infusion function synergistically in facilitating tolerance to allografts. Graft-versus-host disease (GVHD) is one of the major complications of allogeneic bone marrow transplantation (BMT). Recent studies at Dr. Hess laboratory have shown that a novel autoimmune syndrome resembling GVHD, but without significant toxicity, can be induced after autologous BMT.  Some of the findings in ongoing studies were: effector T cells in autologous GVHD recognize MHC class II antigens in association with a peptide from the invariant chain termed CLIP, identification of a novel population of regulatory T cells that suppresses the development of GVHD, and that two terminal flanking domains of CLIP have unique immunological properties. (The Sidney Kimmel Comphresensive Cancer Center, n.d.) Conclusion The Major Histocompatibility Complex (MHC) present on cell surfaces is important in the process of transplant rejection. There are two classes of MHC, Class I and Class II MHC molecules, which show binding specificity. TCR is composed of two chains, alpha and beta, each having separate, constant and variable domains. Antigen recognition by T cells is said to be MHC-restricted. The B-cell antigen receptor (BCR) is made of membrane Igs (mIgs), a heterodimer of Ig (CD79a) and Ig (CD79b) transmembrane proteins. Cytokines are proteins, which help to mediate immunity. However, the activation of cytokine signaling pathways and how they control cell division is not yet clear. The use of immunosuppressive agents in preventing transplant rejection has numerous drawbacks. The pretransplant exposure to donor MHC antigens has been tried in experimental models with successful induction of tolerance. In humans, graft survival has been prolonged by donor bone marrow administration and pretransplant blood transfusion. Improvement in gene therapy will allow use of allogeneic donor bone marrow without graft-versus-host-disease (GVHD). The potential of MHC class II gene transfer, which allows tolerance to solid organ allografts has been demonstrated in one study. Current alternative approaches being tried include total lymphoid irradiation (TLI) and donor bone marrow transfusion combined with anti-lymphocyte globulin (ALG) post-transplantation. It is clear, therefore, that a better understanding of the mechanisms of rejection and tolerance, and the use of gene therapy, donor bone marrow administration and pretransplant blood transfusion techniques, TLI, and ALG may allow transplantation tolerance in the future. References Bazan JF (1990). Structural design and molecular evolution of a cytokine receptor superfamily. Proc. Natl. Acad. Sci. USA 87:6934–38. Cosman D, et al (1990). A new cytokine receptor superfamily. Trends Biochem. Sci. 15:265–70. Decker JM (2003). Immunology. [Online] Retrieved February 10, 2006 from, http://microvet.arizona.edu George AJ, Stark J, Chan C (2005). Understanding specificity and sensitivity of T-cell recognition. Trends Immunol. 2005 Dec; 26(12): 653-9. Immune System Series (n.d). [Online] Retrieved February 10, 2006 from, Major Histocompatibility (n.d). [Online] Retrieved February 10, 2006 from, Payelle-Brogard B, Magnac C et al.(1999). Analysis of the B-Cell Receptor B29 (CD79b) Gene in Familial Chronic Lymphocytic Leukemia. Blood, Vol. 94 No 10, 1999: pp. 3516-3522. Radosevich M, Ono SJ (2003). Novel mechanisms of class II major histocompatibility complex gene regulation. Immunol Res. 2003; 27(1): 85-106. Sears DW, Christensen SR (1997). Major Histocompatibility Complex. [Online] Retrieved February 10, 2006 from, Sonntag KC, Emery DW, et al. (2001). Tolerance to solid organ transplants through transfer of MHC class II genes. J Clin Invest. 2001 Jan; 107(1): 65-71. The Sidney Kimmel Comphresensive Cancer Center (n.d) [Online] Retrieved February 10, 2006 from, http://www.hopkinskimmelcancercenter.org Watowich SS et al. (1996). Cytokine receptor signal transduction and the control of hematopoietic cell development. Annu. Rev. Cell Dev. Biol. 1996. 12:91–128. Wong W and Wood KJ (2004). Transplantation Tolerance by Donor MHC Gene Transfer. Current Gene Therapy. 2004. Vol. 4, No. 3: 329-36. Wood KJ (1991). Alternative approaches for the induction of transplantation tolerance. Immunol Lett. 1991 Jul; 29(1-2): 133-7. Woodley SL, Gurley KE, et al.(1993). Induction of tolerance to heart allografts in rats using posttransplant total lymphoid irradiation and anti-T cell antibodies. Transplantation. 1993 Dec;56(6):1443-7. Read More