Role of Major Histocompatibility Cells in Transplantation

About Authors:
G.Amrutha
Microbiologist in Department Of Microbiology
Institute Of Health Systems (HIS), Hyderabad.
Osmania University

Abstract
Transplantation is the process of removal of damaged tissue or organ and replacing with new well functioning tissue or organ of same or different individual. The groundwork for the new science of transplantation immunology was laid by Medawar and other British biologists in the 1940s. They showed that rejection of tissue transferred from one person or animal to another was invariable, except for grafts between identical twins or a few special cases (e.g. cornea). In the 1950s they further showed that this tissue rejection was a response of the immune system. Other scientists who worked for transplantation are Karl Landsteiner, Dr. Eduard Zirm, Dr. Alexis Carrel, Peter Gorer, Little and Tyzzer, George Snell, Dr. Joseph Murray etc..,Different types of organs like heart,skin,kidney,liver,cornea etc.., can be transplanted. Antigens which cause strong immune response and are most important in rejection of organs and tissues are called MHC antigens which play main role in transplantation. There are mainly 4 types of grafts. They are Autograft,Isograft,Allograft and Xenograft. The rejection may be acute and chronic and the mechanism of graft rejection is of mainly 2 types. They are sensitization stage and effector stage. Finally, the graft survival can be done by mitotic inhibitors, immune suppressive therapy etc..,

Reference Id: PHARMATUTOR-ART-1166

DEFINITIONS

· Histocompatibility (transplantation) antigens
Antigens on tissues and cells that determine their rejection when grafted between two genetically different individuals

· Major histocompatibility (MHC) antigens
Histocompatibility antigens that cause a very strong immune response and are most important in rejection

· MHC complex
Group of genes on a single chromosome encoding the MHC antigens

· HLA (human leukocyte antigens)
MHC antigens of man (first detected on leukocytes)

· H-2 antigens
MHC antigens of mouse

Transplantation is the process of removal of damaged tissue or organ and replacing with new well functioning tissue or organ of same or different individual.The groundwork for the new science of transplantation immunology was laid by Medawar and other British biologists in the 1940s. They showed that rejection of tissue transferred from one person or animal to another was invariable, except for grafts between identical twins or a few special cases (e.g. cornea). In the 1950s they further showed that this tissue rejection was a response of the immune system

Types of graft

Xenograft : Grafts between members of different species (also known as heterologous,xenogeneic or heterografts)

Autograft : Graft transferred from one part of patient’s body to another part

Allograft : Grafts between two members of the same species (also known as allogeneic or homograft)

Isograft : Grafts between members of the same species with identical genetic makeup (identical twins or inbred animals)

Haplotype
A group of genes on a single chromosome

History of Clinical Solid Organ Transplantation
In 1902Karl Landsteiner classifies blood into three groups A, B and O. Group AB later added. This has been described as the beginning of modern Immunogenetics. Blood transfusion can legitimately be considered a type of transplantation. In1905, First Successful Cornea Transplant was performed by Austrian surgeon Dr. Eduard Zirm. In1908, French surgeon Dr. Alexis Carrel develops surgical techniques for sewing arteries and veins which are used in organ transplantation and other surgical procedures today. In1916, Little and Tyzzer in analysing tumour transplants between mice demonstrated that several dominant genes influenced the outcome of allogenic tumour grafts. They were able to show that tumours transplanted from one strain of mice to mice of the same strain were accepted, whereas, tumours transplanted to a different strain were rejected. This was the first in a series of experiments by several researchers over many years that lead to the discovery of the Major Histocompatibility Complex (MHC) and its role in transplantation. (Little, C. C., Tyzzer, E.E. (1916). Further experimental studies on the inheritance of susceptibility to a transplantable tumour, carcinoma (JWA) of the Japanese waltzing mouse. J. Med. Res. 33, 393-453.). In1937, Peter Gorer, working at the Jackson Laboratory discovered an antigen in mice which he named Antigen II. This was later discovered to be the same antigen that George Snell had named Fu and which he had demonstrated played a role in transplant rejection. In collaboration they discovered the genes encoding this antigen and named it H2 (H for histocompatibility and 2 for antigen II). This is the first early picture of what later came to be called the Major Histocompatibility Complex (MHC). The first published use of the term MHC was not until the 1970′s. Later, in1940′s,British zoologist Peter Medawar used experimental skin transplants on animals to explain why burn victims from the bombing of civilians in England during World War II reject donated skin. This work enabled him to establish theories of transplantation immunity. Peter Medawar was awarded the Nobel Prize in Physiology or Medicine in 1960 for the ‘discovery of acquired immunological tolerance’. In 1948 George Snell further characterised the MHC system. He carried out a series of mouse breeding experiments which showed that transplantability was determined by the presence of special antigens on the surface of the cell. He called these histocompatibility antigens. He also showed that these antigens were coded for by genes found within a limited area on chromosome 6. This area was called the major histocompatibility complex (MHC). In 1953, James Watson and Francis Crick, drawing on their own work as well as the unpublished work of others including Maurice Wilkins and Rosalind Franklin, publish ‘The Molecular structure of Nucleic Acids: A Structure for Deoxyribose Nucleic Acid’ in the scientific journal Nature. vol 171 pp 737-738. This was the first published article which described the double helix structure of DNA. Watson, Crick and Wilkins were awarded the Nobel Prize in Physiology or Medicine in 1962 ‘for their discoveries concerning the molecular structure of nucleic acids and its significance for information transfer in living material’. In1954, The first successful living-related donor kidney Transplant was performed. A kidney transplant between 23-year-old identical twins, one of who was dying from advanced glomerulonephritis was performed by Dr. Joseph Murray and Dr. David Hume, Brigham Hospital, Boston. In1958, Jean Dausset describes the first Human leukocyte antigen that he named MAC using leukoagglutination techniques he had earlier described in 1952. He went on to propose a complex system which he designated HU-1 but which was later renamed HLA for ‘Human Leukocyte Antigen’. Jean Dausset was awarded the Nobel Prize in Physiology or Medicine in 1980, together with George Snell and Baruj Benacerraf, for ‘their discoveries concerning genetically determined structures on the cell surface that regulate immunological reactions’.In 1962, First successful deceased donor kidney transplant was performed by Dr. Joseph Murray and Dr. David Hume, Brigham Hospital, Boston. The patient received the new immunosuppressive drug azathioprine and lived for 21 months. In1963, First successful lung transplant was performed by Dr. James Hardy at the University of Mississippi Medical Centre. That same year Jon van Rood discovered the Bw4 and Bw6 series of HLA antigens. In 1964,
Julia and Walter Bodmer, with Rose Payne discovered the LA series of HLA antigens. The LA nomenclature was later to provide the last two letters of what became known as the HLA system. Bernard Amos organised the first International Histocompatibility Workshop. In 1966, The first successful pancreas transplant from a deceased donor takes place. The recipient, who had uncontrolled diabetes and kidney failure, was a patient at the University of Minnesota Medical Centre.In 1967, First successful liver transplant was performed by Dr. Thomas Starzl, University of Colorado, Denver, CO. In 1967, First Successful Heart Transplant was performed by Dr. Christian Barnard, Groote Schuur Hospital, South Africa. The patient, 54-year old Louis Washkansky, received a heart from a 23-year-old woman who died in a car accident. The heart functioned until the patient died of pneumonia eighteen days later because of their suppressed immune system. In1968,The WHO nomenclature committee for factors of the HLA system is set up by Bernard Amos. In 1969-1972, Cyclosporin is isolated from the soil fungus Tolypocladium inflatum and its immunosuppressive capabilities discovered by scientists at Novartis.In 1981,First Successful heart/lung Transplant was performed by Dr. Norman Shumway, Stanford University Medical Centre, Palo Alto, CA.In 1984 – 1987, Tacrolimus is discovered in a soil fungus by a Japanese team. In 1990, Dr Joseph E. Murray (kidney transplant) and Dr E. Donnall Thomas (bone marrow transplantation) are jointly awarded the Nobel Prize in Physiology or Medicine 1990 ‘for their discoveries concerning organ and cell transplantation in the treatment of human disease’

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PRINCIPLES OF TRANSPLANTATION
An immunocompetent host recognizes the foreign antigens on grafted tissues (or cells) and mounts an immune response which results in rejection. On the other hand, if an immunocompromised host is grafted with foreign immunocompetent lymphoid cells, the immunoreactive T-cells in the graft recognize the foreign antigens on the host tissue, leading to damage of the host tissue.

Host-versus-graft-reaction
The duration of graft survival follows the order, xeno- < allo- < iso- = auto- graft. The time of rejection also depends on the antigenic disparity between the donors and recipient. MHC antigens are the major contributors in rejection, but the minor histocompatibility antigens also play a role. Rejection due to disparity in several minor histocompatibility antigens may be as quick or quicker than rejection mediated by an MHC antigen. As in other immune responses, there is immunological memory and secondary response in graft rejection. Thus, once a graft is rejected by a recipient, a second graft from the same donor, or a donor with the same histocompatibility antigens, will be rejected in a much shorter time.

Graft-versus-host (GVH) Reaction
Histocompatible lymphoid cells, when injected into an immunocompromised host, are readily accepted. However, the immunocompetent T lymphocytes among the grafted cells recognize the alloantigens and, in response, they proliferate and progressively cause damage to the host tissues and cells. This condition is known as graft-versus-host (GVH) disease (figure 3) and is often fatal.

Common manifestations (figure 4) of GVH reaction are diarrhea, erythema, weight loss, malaise, fever, joint pains, etc. and ultimately death.

THE MHC GENE COMPLEX
The MHC complex contains a number of genes that control several antigens, most of which influence allograft rejection. These antigens (and their genes) can be divided into three major classes: class I, class II and class III. The class I and class II antigens are expressed on cells and tissues whereas as class III antigens are represented on proteins in serum and other body fluids (e.g.C4, C2, factor B, TNF). Antigens of class III gene products have no role in graft rejection.

Human MHC
The human MHC is located on chromosome 6.

Class I MHC
The class I gene complex contains three major loci, B, C and A and other undefined minor loci (figure 5). Each major locus codes for a polypeptide; the alpha-chain that contains antigenic determinants, is polymorphic (has many alleles). It associates with beta-2 microglobulin (beta-chain), encoded by a gene outside the MHC complex, and expressed on the cell surface. Without the beta-2 microglobulin, the class I antigen will not be expressed on the cell surface. Individuals with a defective beta-2 microglobulin gene do not express any class I antigen and hence have a deficiency of cytotoxic T cells.

Class II MHC
The class II gene complex also contains at least three loci, DP, DQ and DR; each of these loci codes for one alpha- and one beta-chain polypeptide which associate together to form the class II antigens. Like the class I antigens, the class II antigens are also polymorphic. The DR locus may contain more than one, possibly four, functional beta-chain genes.

Mouse MHC The mouse MHC is located on chromosome 17.

Class I MHC
This consists of two major loci, K and D. Unlike the human MHC, the mouse class I gene complexes loci are not together but they are separated by class II and class III genes (Figure 6A).

Class II MHC
The class II gene complex contains two loci, A and E, each of which code for one alpha and one beta chain polypeptide, which form one class II molecule. The mouse class II gene complex is also known as the I region and the genes in this complex are referred to as Ir (immune response) genes since they determine the magnitude of immune responsiveness of different mouse strains to certain antigens. Products of the A and E loci are also termed IA and IE antigens, collectively known as Ia antigens.

MHC ANTIGENS
Nomenclature
HLA specificities are identified by a letter for locus and a number (A1, B5, etc.) and the haplotypes are identified by individual specificities (e.g., A1, B7, Cw4, DP5, DQ10, DR8). Specificities which are defined by genomic analysis (PCR), are names with a letter for the locus and a four digit number (e.g. A0101, B0701, C0401 etc). Specificities of mouse MHC (H-2) are identified by a number. Since laboratory mice are inbred, each strain is homozygous and has a unique haplotype. The MHC haplotype in these strains is designated by a 'small' letter (a, b, d, k, q, s, etc.); for example, the MHC haplotype of Balb/c mice is H2^d.

Inheritance
MHC genes are inherited as a group (haplotype), one from each parent. Thus, a heterozygous human inherits one paternal and one maternal haplotype, each containing three class-I (B, C and A) and three class II (DP, DQ and DR) loci. A heterozygous individual will inherit a maximum of 6 class I specificities (Figure 6). Similarly, the individual will also inherit DP and DQ genes and express both parental antigens. Since the class II MHC molecule consists of two chains (alpha and beta), with some antigenic determinants (specificities) on each chain, and DR alpha- and beta-chains can associate in ether cis (both from the same parent) or trans (one from each parent) combinations, an individual can have additional DR specificities (Figure 6B). Also, there are more than one functional DR beta-chain genes (not shown in the figure). Hence, many DR specificities can be found in any one individual.

Crossover
Haplotypes, normally, are inherited intact and hence antigens encoded by different loci are inherited together (e.g., A2; B27; Cw2; DPw6; DQw9; DRw2). However, on occasions, there is crossing over between two parental chromosomes, thereby resulting in new recombinant haplotypes. Thus, any one specificity encoded by one locus may combine with specificities from other loci. This results in vast heterogeneity in the MHC make-up in a given population.

MHC antigen expression on cells
MHC antigens are expressed on the cell surface in a co-dominant manner: products of both parental genes are found on the same cells. However, not all cells express both class I and class II antigens. While class I antigens are expressed on all nucleated cells and platelets (and red blood cells in the mouse), the expression of class II antigens is more selective. They are expressed on B lymphocytes, a proportion of macrophages and monocytes, skin associated (Langerhans) cells, dendritic cells and occasionally on other cells.

MHC detection by serological test
The MHC class I antigens are detected by serological assays (Ab and C). Tissue typing sera for the HLA were obtained, in the past, from multiparous women who were exposed to the child's paternal antigens during parturition and subsequently developed antibodies to these antigens. More recently, they are produced by monoclonal antibody technology. With most laboratories switching to PCR for tissue typing, the use of serology is rapidly diminishing.

MHC detection by mixed leukocyte reaction (MLR)
It has been observed that lymphocytes from one donor, when cultured with lymphocytes from an unrelated donor, are stimulated to proliferate. It has been established that this proliferation is primarily due to a disparity in the class II MHC (DR) antigens and T cells of one individual interact with allogeneic class-II MHC antigen bearing cells (B cells, dendritic cells, langerhans cells, etc.). This reactivity was termed mixed leukocyte reaction (MLR) and has been used for studying the degree of histocompatibility. In this test, the test lymphocytes (responder cells)are mixed with irradiated or mitomycin C treated leukocytes from the recipient, containing B-lymphocytes and monocytes (stimulator cells). The cells are cultured for 4 6 days. The responder T cells will recognize the foreign class II antigens found on the donor and undergo transformation (DNA synthesis and enlargement: blastogenesis) and proliferation (mitogenesis). The T cells that respond to foreign class II antigens are typically CD4+ TH-1 type cells. These changes are recorded by the addition of radioactive (tritiated, 3H) thymidine into the culture and monitoring its incorporation into DNA.

Generation of cytotoxic T lymphocytes
Another consequence of the MHC antigen and T cell interaction is the induction of cytotoxic T-lymphocytes. When T-lymphocytes are cultured in the presence of allogeneic lymphocytes, in addition to undergoing mitosis (MLR), they also become cytotoxic to cells of the type that stimulated MLR (figure 7). Thus, T-lymphocytes of 'x' haplotype cultured over 5 - 7 days with B lymphocytes of 'y' haplotype will undergo mitosis and the surviving T-lymphocytes become cytotoxic to cells of the 'y' haplotype. The induction of mitosis in MLR requires disparity of only class II antigens whereas the induction of cytotoxic T-lymphocytes (CTL) requires disparity of both class I and class II antigens. However, once cytotoxic cells have been induced, the effector cytotoxic cells recognize only class I antigens to cause cytotoxicity.

Mechanism Of Graft Rejection
Graft rejection is mainly caused by cell mediated immune response to allo antigens expressed on cell of the grafts.Both delayed type hyper sensitive and cell mediated cytotoxicity reactions have been implicated.The process of graft rejection can be divided into two stages:

Sensitization stage, antigen reactive lymphocytes proliferate in response to alloantigens on the graft

Effector stage, in which immune destruction of the graft takes place.

Sensitization stage
During the sensitization stage, CD4+ and CD8+ T cells recognize alloantigens expressed on the cells of foreign graft and proliferate in response.Both major and minor Histocompatibility genes can be recognized.The response to MHC antigens involves recognition of both donor MHC molecule and associated peptide ligand in the cleft of the MHC molecule.The peptide present in the groove of class1 MHC molecule are derived from proteins synthesized in allogenic cell. The peptides present in the groove of class2 MHC molecule are taken up and processed by endocytic pathway of allogenic antigen presenting cell. A host TH cell becomes activated when it interacts with APC that expresses an antigen ligand-MHC molecule and provides costimulatory signal. Depending upon the type of tissue,different cells within graft may act as APC.Dendritic cells are the major APC in graft. APC of host origin also migrate into the graft and endocytocise the foreign alloantigen and produce them as processed peptides together with self MHC molecule.In some organ and tissue grafts,(Ex: grafts of kidney,Thymus and Pancreatic islets), a population of donor APC, called passenger leukocytes had been showed to move from graft to regional lymph node. These passenger leukocytes are dendritic cells, which show high levels of class II MHC molecules and arr wide spread in animal tissues with exception of brain. Because ,passenger leukocytres expresses allogenic MHC antigen of donor graft, they are recognized as foreign and therefore stimulate immune activation of T lymphocytes in lymph nodes. Other cell types that implicate in immune stimulation besides these passenger leukocytes are Langerhans and endothelial lining the blood vessels. The degree and type of immune response varies with the transplant. Some transplants, so called immunologically previlaged sites like eye and brain donot encounter cells of immune system and may be tolerated despite mismatch of genetic types.This is not true for most allograft. For example when skin, which has no blood vessels is grafted, at first it does not contain any blood vessels. As these establish host lymphocytes carried to the tissues by capillaries or lymphatics encounter the foreign antigens of skin graft and are carried by afferent lymphatics to regional lymph nodes. Effector lymphocytes are generated in regional lymph nodes and are carried by lymphatics back to graft to inculcate a immune response.In kidney or heart transplants, the blood vasculature is immediately restored.Because it is necessary to suture the major blood vessels of graft together with those of the host. In this case the blood borne lymphocytes encounter the alloantigens of the graft and are carried by blood vessels to spleen or lymphatic vessels to lymph nodes. Within spleen or lymph nodes, effector cells are generated and are transported back to graft by blood or lymph vessels.Recognition of alloantigens induce T-cell proliferation in the host. Both dendritic cells and vascular endothelial cells induce T-cell proliferation. The major one is CD4+ Tcell which recognize class II alloantigens directly.This amplified population of Tcell thought to play a central role in producing various effector mechanisms of allograft rejection.

Effector Stage
A variety of effector mechanisms participate in allograft rejection. The most common are cell mediated immunity involving Delayed type Hypersensitivity and CTL mediated Cytotoxicity.Less common mechanisms are antibody plus-complement lysis and Destruction by antibody dependent cell mediated cytotoxicity(ADCC).Cytokines secreted by TH cells plays an important role in effector mechanisms. For example IL-2,IFN, TNF have each been shown as important mediators for graft rejection. IL-2 promotes Tcell proliferation and generally necessary for generation of effector CTLs. IFN is centrally responsible for promotion of DTH response,promoting the influx of macrophage into the graft and their subsequent activation into the more destructive cells. TNF have been shown to have direct cytotoxic effect on the cells of the graft. A number of cytokines promote graft rejection by promoting class I and class II MHC molecules. In rat cardiac allograft, dendritic cells are the only cells that express class II MHC molecules. However as allograft reaction begins, localized production of IFN-y in the graft induces vascular endothelial cells and myocytes to express class II MHC molecules as well making these cells target for CTL attack.

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ALLOGRAFT REJECTION
The clinical significance of the MHC is realized in organ transplantation. Cells and tissues are routinely transplanted as a treatment for a number of diseases. However, reaction of the host against allo-antigens of the graft (HVG) results in its rejection and is the major obstacle in organ transplantation. The rejection time of a graft may vary with the antigenic nature of the graft and the immune status of the host and is determined by the immune mechanisms involved.

Hyper-acute rejection
This occurs in instances when the recipient has preformed high titer antibodies. A graft may show signs of rejection within minutes to hours due to immediate reaction of antibodies and complement.

Accelerated (2nd set; secondary) rejection
Transplantation of a second graft, which shares a significant number of antigenic determinants with the first one, results in a rapid (2 - 5 days) rejection. It is due to presence of T-lymphocytes sensitized during the first graft rejection. Accelerated rejection is mediated by immediate production of lymphokines, activation of monocytes and macrophages, and induction of cytotoxic lymphocytes.

Acute (1st set; primary) rejection
The normal reaction that follows the first grafting of a foreign transplant takes 1 - 3 weeks. This is known as acute rejection and is mediated by T lymphocytes sensitized to class I and class II antigens of the allograft, elicitation of lymphokines and activation of monocytes and macrophages.

Chronic rejection
Some grafts may survive for months or even years, but suddenly exhibit symptoms of rejection. This is referred to as chronic rejection, the mechanism of which is not entirely clear. The hypotheses are that this may be due infection, causes which led to failure of the first organ, loss of tolerance induced by the graft, etc.

Fetus as an Allograft
The fetus in an out-bred mammalian species bears antigens derived from both the father and the mother. Thus, truly, the fetus is an allograft and the mother should normally recognize the fetus as foreign and reject the fetus. Nonetheless, such rejections seldom occur. Thus, mammals have adapted in a way that allows implantation of their embryos in the mother's womb and their subsequent survival. There are multiple mechanisms that play a role, of which the most important being the unique structure and function of placenta.

Immunologically privileged sites and tissues
There are certain locations in the body in which allografts are not readily rejected. These include the brain, anterior chamber of the eye, testis, renal tubule, uterus, etc. This stems from the fact that such sites may lack of good lymphatic drainage. Also, such tissues may express molecules such as Fas ligand that kills any immune cell that may come in contact with these tissues. Additionally, such tissues, may have other immune suppressor mechanisms. Similarly, there are some tissues that can be transplanted without matching and without being rejected. Such tissues are called immunologically privileged tissues. Corneal graft is an excellent example that enjoys the highest success rate of any form of organ transplantation. The low incidence of graft rejection is impressive despite the fact that HLA antigen matching of donor and recipient is not normally performed. There are many explanations as to why such grafts are accepted. The avascularity of the graft bed prevents corneal alloantigens from reaching the regional lymphoid tissues. Also, the corneal antigens may be masked. Together, such mechanisms fail to activate the immune system of the recipient.

PROCEDURES TO ENHANCE GRAFT SURVIVAL
In clinical practice, the most successful transplantation programs have been with kidneys and corneas. However, other organs are being transplanted with increasing frequency. The success in these programs has been due to a better understanding of immunological mechanisms, definition of MHC antigens and development of more effective immunosuppressive agents.

Donor selection
Based on extensive experiences with renal transplants, certain guidelines can be followed in donor selection and recipient preparation for most organ transplants. The most important in donor selection is the MHC identity with the recipient; an identical twin is the ideal donor. Grafts from an HLA-matched sibling have 95-100% chance of success. One haplotype-identical parent or sibling must match at the HLA D region. A two haplotype-distinct donor with a reasonable match for D-region antigen can also be used. Organs from a two or one DR matched cadaver have been used also with some success. In every case, an ABO compatibility is essential.

Recipient preparation
The recipient must be infection-free and must not be hypertensive. One to five transfusions of 100-200 ml whole blood from the donor at 1-2 week intervals improves the graft survival and is practiced when possible.

Mitotic Inhibitors

Azathioprine(imuran), a potent mitotic inhibitor is given before and after transplantation to diminish Tcell proliferation in response to alloantigen of the graft.Azathioprine acts on S phase of cell cycle to block the synthesis of Inosinic acid which is precursor of purines Adenylic and Guanylic acid. Two other mitotic inhibitors that acts in conjunction with other immunosuppressive agents are Cyclophosphamide and Methotrexate. Cyclophosphamide is an alkylating agent that inserts into the DNA double helix and becomes crosslinked leading to disruption of DNA chain. It is especially effective at rapidly dividing cells and therefore given at the time of grafting to block T cell proliferation. Methotrexate, acts as folic acid antagonist to block purine biosynthesis.

Corticosteroids
Corticosteroids such asPrednisone andDexamethasone are potent anti inflammatory agents that exerts their effects in many levels of immune response. These drugs are given to transplant recipients along with mitotic inhibitors like Azathioprine to prevent acute episodes of graft rejection.

Fungal MetabolitesCyclosporin A(CSPA), FK506 AND Rapamycin are Fungal metabolites with potent immune suppressive properties. Although, chemically unrelated both shows similar action.Both drugs blocks the activation of resting Tcells by inhibiting the transcription of genes encoding IL-2 and IL-2 receptor which are essential for activation.

Total Lymphoid Irradiation
Because lymphoids are extremely sensitive to Xrays ,X irradiation can be used to eliminate them in transplant recipient just before grafting. In total lymphoid X-irradiation the recipient receives multiple X rays exposure to Thymus, Spleen,Lymph nodes before the transplant surgery.The typical protocol is daily exposure to Xrays of about 200rads per day upto several weeks till3400 rads has been administered.Because, the Bonemarrow is not X-irradiated, lymphoid stem cells proliferate and renew the population of recirculating lymphocytes.These newly formed lymphocytes appeared to be more tolerant to the antigens of the graft.

Immunosuppressive Therapy
Immunosuppressive therapy is most essential part of allo-transplantation. The most recent and effective family of agents is cyclosporin A, FK-506 (tacrolimus) and rapamycin. Cyclosporin A and FK506 inhibit IL-2 synthesis following Ag-receptor binding whereas rapamycin interferes with signal transduction following IL2 - IL2 receptor interaction. Thus, all three agents block T cell proliferation in response to antigen. Other chemical agents used to prevent graft rejection and their modes of action have been listed in Table 2. Whole body irradiation is used in leukemia patients before bone marrow transplantation. Antisera against T cells (anti-thymocyte globulin: ATG) or their surface antigens (CD3, CD4, CD45 on activated T-cells, CD25:IL-2 receptors) are being used also to achieve immunosuppression

Strategies for bone marrow transplantation
In bone marrow transplantation, the most crucial factor in donor selection is class II MHC compatibility. Once again an identical twin is the ideal donor. From poorly matched grafts, T lymphocytes can be removed using monoclonal antibodies (figure 10). The recipient must be immunosuppressed. Malignant cells must be eliminated from the recipient blood (in case of blood-borne malignancies). Methotrexate, cyclosporin and prednisone are often used to control GVH disease.

Other grafts
Corneal grafts do not contain D region antigens and consequently survival is frequent. Small grafts are better and corticosteroids are helpful. Skin allografts have a very poor success rate and immunosuppressive therapy is relatively ineffective. Nevertheless, they are often used to provide a temporary covering to promote healing in severe skin damage. Indeed, there will be no rejection if the host and donor are perfectly matched (identical twins) or the recipient is tolerant to the donor MHC antigens (bone marrow chimeras).

MHC association with diseases
A number of diseases have been found to occur at a higher frequency in individuals with certain MHC haplotypes. Most prominent among these are ankylosing spondylitis (B27), celiac disease (DR3) and Reiter's syndrome (B27). Other diseases associated with different specificities of the MHC are listed in Table 3. No definite reason is known for this association. However, several hypotheses have been proposed: antigenic similarity between pathogens and MHC, antigenic hypo- and hyper-responsiveness controlled by the class II genes are included among them.

The immune response to an allogeneic organ transplant is orders of magnitude greater than the nominal immune response because of:

alloantigen - individual HLA/MHC peptides that recruit recipient T cells
the vast number of T cell clones recruited to the response
antigen presentation by donor APCs (direct antigen presentation) and by recipient APCs (indirect antigen presentation).

Until tolerance can be routinely established in all types of solid organ transplant recipients, the success of transplantation will continue to depend largely on the utmost respect for the powerful and complex forces of the human immune system and chronic administration of immunosuppressive therapy. Although the repertoire of agents at our disposal is ever-increasing and ever-improving, clinicians remain faced with the challenge of attaining the often-elusive balance between preventing rejection and imposing drug-related toxicity.

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