Structure of The Major Histocompatibiltiy Complex (MHC) - Essay Example

Major Histocompatability Complex and transplantation - New development Structure of The Major Histocompatibiltiy Complex (MHC) The Major Histocompatibiltiy Complex (MHC) is a large genomic region or gene family found in most of the vertebrates. A greater proportion of these genes is related to the immune system of the body. In humans the span of the MHC complex is almost 4 megabases located at chromosome 6. There are total of approximately 200 known genes and about 50 percent of them have got known functions. The complex has been further divided in subgroups of two classes MHC class I and MHC class II. There are three class I -chain genes, called HLA-A, -B, and-C, and three pairs of class II -chain & -chain genes, called HLA-DR, -DP, and -DQ (Bowers 2004) (Wikipedia 2006). Figure 1. The genetic organization of the major histocompatibility Complex (MHC) in human and mouse. Source (Janeway 2001) Functions of MHC The functions performed by the complex are: binding of peptide fragments from invading pathogens and then displaying these peptide fragments on the cell surface so that it should be recognized by T-cells fro further degradation. Figure 2.T-cell recognition of antigens is MHC restricted. Source (Janeway 2001) MHC has got two unique properties, which make it difficult for any pathogen to evade immune responses in this way. These are:i) the MHC is polygenic: there are different varieties of MHC class I and MHC class II genes, hence every individual has got a set of MHC molecules with different ranges of peptide-binding specificities.ii) the MHC is highly polymorphic; there are multiple variants of each gene within the population as a whole. The MHC genes are, in fact, the most polymorphic genes known (Janeway 2001). It has become an important and more frequent clinical practice to replace diseased organs through transplantation. The response of the body to tissues with nucleated cells is more severe, as compared to blood transfusion containing anucleated RBCs, and it is the response of T-cells to highly polymorphic MHC molecules. This can be achieved by matching of the MHC type between donor and recipient that is not possible to 100%. (Janeway 2001) Graft rejection is an immunological response with primary involvement of T cells A major problem posed to the tissue transplantation is by immune responses. First Set Rejection Whenever any tissue like, skin, is grafted the body accepts it initially but the it is rejected in next ten days to two weeks time. T-cells are the major component of this immune system. Second Set Rejection Previously rejected graft from a donor decreases the probability of acceptance of the second graft from the same donor to the same recipient and this response even earlier than the first set reject when body rejects it within a week time. This is again mediated by CD8 T cells, by CD4 T cells, or by both and at times even antibodies also become a part of this team (Janeway 2001). Matching donor and recipient at the MHC When donor and recipient differ at the MHC, the immune response, which is known as an alloreactive response as it is directed against antigens (alloantigens) that differ between members of the same species, is directed at the nonself allogeneic MHC molecule or molecules present on the graft. Most tissues contain predominantly MHC class I antigens. Once a graft is rejected due to presence of a particular MHC type, the second graft with the same nonself MHC molecule will also be rejected in a second-set response in a rapid manner. This is because of the frequency of T cells specific for any nonself MHC molecule that is very high, making differences at MHC loci the most potent trigger of the rejection of initial grafts (Janeway 2001). In human, HLA matching significantly improves the success rate of clinical organ transplantation but even it cannot in itself prevent rejection reactions. There are two main reasons behind this phenomenon: a) HLA typing is imprecise, owing to the polymorphism and complexity of the human MHC; unrelated individuals who type as HLA-identical with antibodies against MHC proteins rarely have identical MHC genotypes. As siblings inherit their MHC genes as a haplotype this is problem is rarely seen there, b) differences between minor histocompatibility antigens also rejects the graft but at a very slow pace. Thus, unless donor and recipient are identical twins, all graft recipients must be given immunosuppressive drugs to prevent rejection (Janeway 2001). MHC plays a significant role in the process of organ transplantation. Development carried out in relation to MHC in transplantation is as old as organ transplantation is itself. There has been an immense level of research and subsequent development carried out in this field. We cannot encompass the whole area of the research but will focus mainly on the following topics as far as the development is concerned in this area: 1. Role of anatomical structures or physiological/biochemical processes 2. Drugs 3. Graft-versus-host-disease (GVHD) 4. Other topics Role of anatomical structures or physiological/biochemical processes The importance of endothelial cells in the regulation of the inflammatory process cannot be overlooked. These microscopic structures behave in a similar way, as that of inflammation, to any transplanted organ; by recruiting leukocytes and affecting T-cells, activation of complement pathways, proliferation of endothelial cells by contact with anti-HLA antibodies, production of protective chemicals after antibodies contact and endothelial cells proliferation (Anna & Peter 2003). In another study carried by Jing et al., it has been concluded through intracellular signalling that ligation of anti-HLA Ab to MCH class I molecule results in a couple of chemical reactions as: tyrosine phosphorylation of various protein tyrosine kinases (PTK) which also includes focal adhesion kinases (FAK). FAK has got a very important role in cell growth and survival. This is achieved by the activation of PI3 kinase/Akt signalling pathway and regulation of expression of anti-apoptotic proteins on endothelial cells of graft (Jin 2004). The soluble HLA has got double role in the immune system of the human body; it acts as immunosupresser at one end and takes part in delayed type hypersensitivity responses at the other end. In graft cells, which have been infected with Cytomegalovirus (CMV), HLA is released from infected cells while s|HLA is released by uninfected bystander cells (Haynes 2005). Antibody specificity is an important requirement for any individual who is a candidate for transplantation or platelet transfusion and needs a donor. This process becomes difficult due to the presence of some confounders. The single antigen-expressing (SAL) cell lines have been proved to be an important and appropriate mechanism which determines the acceptable mismatches for highly sensitised patients. The SALs have been generated by transferring human MHC class I sequences in K562 which is an erythro-leukemia-derived cell line lacking MHC class I & II expression. Sixteen SAL out of thirty-seven have been validated through cytometry against 84 human HLA specific monoclonal antibodies (Zoet 2005). Drugs Cyclosporine has been used to suppress graft rejection. But its use has been discouraged due to its side effects. Various studies have, time and again, explored and concluded either its inability to be proved as a beneficial chemical at therapeutic doses or its side effects. Farzad concludes in his study regarding Heart allograft where cyclosporine could not control vasculopathy at therapeutic doses, it has got no effect on complement system, which causes damage to arteries in the allograft (Moien 2003). In a review carried by Rita explored the role of cyclosporine in causing damage to almost all vital organs in the body. It has got acute and chronic toxic effects on kidneys, toxic effects on liver, heart, and pancreas (Rezzani 2004). Junji et al examined the role of cyclophosphamide in bone marrow chimerism and tolerance without damaging the graft. They were able to define an optimal dose of 150 mg/kg for induction of haematopoietic chimerism and tolerance to transplant (Okayama 2004). Graft-versus-host-disease (GVHD) Among the limitations of transplantation, GVHD stands at the very initial stages. The immune mechanism involved in it is very complex and has not been fully understood. This is a unique characteristic of bone marrow transplantation (Pavan 2003). Whatever has been explored to date is that the T-lymphocytes carried by the bone marrow from donor initiate this phenomenon by attacking the host tissues (Andreoli et 2004) . This disease results in morbidity, which affects the life of the patient to a considerable extent. The disease has been divided in two phases, acute and chronic, based on the appearance of the manifestations of the pathological process. Acute phase appears within 2-6 weeks of the allogenic BMT and affects various organs including skin, liver, pancreas, GIT and mucus membrane. On the other hand, the chronic phase is a late onset phenomenon, which reflects its effects by presenting different clinical features like: scleroderma, liver failure, immune complex diseases and autoantibody formation (Ichiki 2006). John et al. has described the role of different cellular components of the immune system including NK cells alongwith T cells. NK cells have got both the inhibitory as well as activating receptors with diverse specificities. The former receptors provide the characteristics of discriminating ability to these cells through which they can differentiate between MHC class I-positive and -negative target cells. Because of this ability they are involved in the control of NK cell tolerance to self. They have got the ability to eliminate the cells which have got downregulation of MHC class I molecules (Barao 2003). Based on the behaviour of these cells, they have been categorized to represent GVHD and Graft-versus-leukaemia (GVL). T cells are the major effectors of GVHD while NK cells of GVL. GVL has got its basics similar but opposite to GVHD. Recipients with malignancy present their cells to the T cells from the donor and induce leukaemia -specific T-cells expansions and these T cells lines have been successfully utilized to treat leukaemia (John et 2003) . If Tells taking part in the development of GVHD are specifically targeted and destroyed, the GVHD may decrease in severity and frequency. Kappel et al successfully discovered the answer. This group introduced tetrameric MHC-peptide complexes, which are used to detect and quantify the antigen specific T-cells populations by the use of cytometry. This way they were able to deplete the specific group of T cells through tetrameric MHC-peptide complexes, which were active in GVHD (Kappel 2006). Chemokines is a group of cytokines and are involved in the immune system movements and functions The role of CCR5 in the development of GVHD is controversial. Its absence on donor cells has been resulted in the morbidity in case of liver and kidney transplantation through CD8+ T cell expansion. Lisbeth et al were also able to show that the recipient of CCR5 donor cells end up with renal lesions and liver problems (Welniak 2004). Others One of the major problems in transplantation is rejection of the graft, which is a natural response of the recipient's body to any new or strange tissue. This graft rejection has been achieved by the introduction of suppression of this response. Most of the time this is achieved by advising steroids and other immuno-suppressant drugs. In turn these have got their own side effects. These effects result in infections, most of the time pulmonary infections. This condition further increases the morbidity and burden on the recipient's health status (Michael 2005). Recipients, who receive the organ from some unrelated donor, usually, face a disparity issue of HLA-A, B, and C alleles. Some of these are serologically detectable. Effie et al, worked on MHC in relation to haematopoietic cell transplantation and found that: those mismatches of HLA class I antigen which are serologically detectable present an increased risk of graft failure after haematopoietic-cell transplantation. While those donors who are with a single class I allele mismatch which is not detectable serologically may be used without an increased risk of failing the graft (Effie et al 2001) Clinical transplantation has become a routine procedure. For a successful transplantation a combination of three important players should be ensured: MHC matching, immunosuppressive drugs, and technical skill. As other genetic differences between host and donor can lead to allogeneic proteins whose peptides are presented as minor H antigens by MHC molecules on the grafted tissue, and responses to these can lead to rejection, hence even an accurate MHC matching does not prevent graft rejection. Therefore, generalized immunosuppression of the recipient becomes an integral step for successful transplantation. Unfortunately, this may lead to the increased risk of cancer and infection because of the toxicity produced by these suppression measures. To date, there has been a huge amount of work done in the field of major histocompatibility complex and its relation with the transplantation. This work can never be documented at one place or talked about in one sitting. It needs a lot of time to discuss this diverse area of medical specialty, which is composed of different specialties. At the moment what is needed is to get benefited what is available under this umbrella. There are so many issues, which can be talked, discussed for further exploration and research. This way the process of learning goes on. Reference: Andreoli E, Carpenter C, Griggs R & Loscalzo J. "Cecil Essentials of Medicine", 6th edn, Saunders, Pennsylvania. Anna Valujskikh and Peter S Heeger. "Emerging role of endothelial cells in transplant rejection." Curr Opin in Immun. 2003;15:493-498 Barao I, Murphy WJ. "The immunobiology of natural killer cells and bone marrow allograft rejection." Biol Blood Marrow Transplant. 2003 Dec;9(12):727-41. Review. Bowers W. "Microbiology and Immunology: on-line." 21 June 2004. University of South Carolina, 08 March 2006. Duncan D and Wilkes D. "Transplant-related immunosuppression". Sep 2005; vol2: 449-455. Effie W. Petersdorf, M.D., John A. Hansen, M.D., Paul J. Martin, M.D., Ann Woolfrey, M.D., Mari Malkki, Ph.D., Theodore Gooley, Ph.D., Barry Storer, Ph.D., Eric Mickelson, B.S., Anajane Smith, M.S., and Claudio Anasetti, M.D. "Major-Histocompatibility-Complex Class I Alleles and Antigens in Hematopoietic-Cell Transplantation." New Eng J Med. 2001 Dec; 345:1794-1800 Haynes LD, Waldman WJ, Bushkin Y, Love RB, Burlingham WJ. "CMV-infected allogeneic endothelial cells initiate responder and bystander donor HLA class I release via the metalloproteinase cleavage pathway." Hum Immunol. 2005 Mar;66(3):211-21. Ichiki Y, Bowlus CL, Shimoda S, Ishibashi H, Vierling JM, Gershwin ME. "T cell immunity and graft-versus-host disease (GVHD)."Autoimmun Rev. 2006 Jan;5(1):1-9. Epub 2005 Apr 21. Janeway C, Travers P, Walport M, Shlomhik M. "The Major Histocompatibility Complex." 2001. Immunobiology. 08 March 2006. Jin YP, Fishbein MC, Said JW, Jindra PT, Rajalingam R, Rozengurt E, Reed EF." Anti-HLA class I antibody-mediated activation of the PI3K/Akt signaling pathway and induction of Bcl-2 and Bcl-xL expression in endothelial cells." Hum Immunol. 2004 Apr;65(4):291-302. Kappel BJ, Pinilla-Ibarz J, Kochman AA, Eng JM, Hubbard VM, Leiner I, Pamer EG, Heller G, van den Brink MR, Scheinberg DA. "Remodeling specific immunity by use of MHC tetramers: demonstration in a graft-versus-host disease model." Blood. 2006 Mar 1;107(5):2045-51. Major Histocompatibility Complex. Wikipedia, the free encyclopedia. 27 Feb 2006. Moien-Afshari F, McManus BM, Laher I. " Immunosuppression and transplant vascular disease: benefits and adverse effects." Pharmacol Ther. 2003 Nov;100(2):141-56. Review. Okayama J, Ko S, Kanehiro H, Kanokogi H, Hisanaga M, Ohashi K, Sho M, Nagao M, Ikeda N, Kanamura T, Akashi S, Nakajima Y. "Bone marrow chimerism and tolerance induced by single-dose cyclophosphamide." J Surg Res. 2004 Jul;120(1):102-10. Pavan Reddy and James Ferrara. "Immunology of acute graft-versus-host-disease." Blood Rev. 2003;17:187-194 Rezzani R. "Cyclosporine A and adverse effects on organs: histochemical studies." Prog Histochem Cytochem. 2004;39(2):85-128. Review. Ruggeri L, Capanni M, Mancusi A, Martelli MF, Velardi A. "The impact of donor natural killer cell alloreactivity on allogeneic hematopoietic transplantation." Transpl Immunol. 2005 Aug;14(3-4):203-6. Review. Welniak LA, Wang Z, Sun K, Kuziel W, Anver MR, Blazar BR, Murphy WJ. "An absence of CCR5 on donor cells results in acceleration of acute graft-vs-host disease." Exp Hematol. 2004 Mar;32(3):318-24. Zoet YM, Eijsink C, Kardol MJ, Franke-van Dijk ME, Wilson GL, de Paus R,Mickelson E, Heemskerk M, van den Elsen PJ, Claas FH, Mulder A, Doxiadis II. "The single antigen expressing lines (SALs) concept: an excellent tool for screening for HLA-specific antibodies."Hum Immunol. 2005 May;66(5):519-25. Read More