Current Devepolments and the Importance of the Major Histocompatibility Complex in Transplantation - Term Paper Example

Introduction In the life that we live, health is considered as that most important aspect of consideration for every human being. When the health of a person will be perfect, he will be able to cop with all other matters of life effectively and efficiently. But when the health becomes to decline, a person becomes unable to deal appropriately with various important matters of life. In order to keep the body perfect and protective against various sorts of diseases, immune system plays a critical role in protection of different infections. So, it is crucial for the health of a person to have a perfect immune system in the body in order to maintain the level of health and to be protective against various infections and diseases. Immunology Before probing into the issue of discussing current developments regarding histocompatibility complex and then describing the importance of histocombatibility complex in transplantation, we should first get to know what immunology actually is. So starting with immunology, it is that sort of study that typically deals with the resistance against various diseases with the immune system. Pathak and Palan (2005) found that it is the study of human immune system and also it is the field of medicine that has a relation with treatment of those diseases which are related to the immune system. Various types of immunology include clinical immunology, developmental immunology, classical immunology, diagnostic immunology, experimental immunology, reproductive immunology and evolutionary immunology. If we talk about immunity, it is the system or mechanism which deals with certain diseases whereas immune system is that sort of network that consists of such systems of the body which have an interaction with each other. Such systems include lymph system, the skin, white blood cells and the bone marrow. Male (2003) found that immunology is a very broad field of medicine study because of the wideness of immune system as it involves everything from the blood cells of the body to even the skin. While talking about immunology, we must also mention those categories of diseases which fall under the immunology. Such categories include very harmful and deadly disease like AIDS and treatment of not so complex skin allergies. Diseases related to immunology Some common diseases related to the field of immunology are asthma and arthritis. These diseases of the immune system are caused due to the body’s hypersensitivity level to various substances. There also exist such disorders which are not possible to deal with only the help of body’s immune system or we can say that such diseases need some sort of external assistance along with the body’s immune system in order to be dealt perfectly. The most obdurate or obstinate problem related to the field of immunology is the disease of AIDS, Acquired Immunodeficiency Syndrome, that attacks the immune system of the body itself and is caused by HIV, Human Immunodeficiency Virus. Effect of AIDS on body If we talk about the effect of this harmful disease, AIDS, on the human body, we can say that it makes the body so much suspicious to the diseases and infections so that the body doest remain in the position to defense different types of diseases. It makes the body in the state of mistrust and defensive system becomes unstable. Eales (2003) found that various vulnerable, susceptible and harmful infections and diseases can attack various organs of the body which results in weakening and declining the patient’s health. It is because AIDS affects the immune system of the body which works as the shield against various types of diseases. So when the immune system gets attacked and ineffective due to the disease of AIDS, it becomes unable to protect the body against certain infections and diseases. Currently there is no cure as such present for the treatment of AIDS but there exist a variety of drug therapies which provide some help in prolonging the life of the AIDS patient by strengthening the immune system of the body but these therapies can’t assure a proper and effective treatment of AIDS. Role of an immunologist While talking about immunology, we must also talk about the role of an immunologist in this field of biomedical science. An immunologist is that specialized person in the field of immunology, who not only measures of antibodies but also performs blood studies and investigates or scrutinizes the transplant rejections. An immunologist also studies those components which are related to the immune system of the body. In order to develop improved and better treatments for the immune system of the body, immunologists work in collaboration with other clinical immunologists who provide help for the treatment of diseases like AIDS and other allergies or infections with the use of various sophisticated molecular techniques by analyzing the components of blood to measure antibodies, immune complexes, immunoglobulin levels and proteins. Major histocompatibility complex and role in transplantation If we talk about major histocompatibility complex, we can say that it is that area of genome that codes for a series of proteins. And that series of proteins are expressed on the cells in the body of a human being which serve as flags for the immune system of the body for the purpose of allowing the immune system of the body to differentiate between the self proteins and the non self proteins. Self proteins are those which are already present in the body whereas non self proteins are those which are foreign. The proteins that are produces by the major histocompatibility complex interface with the T cells of the immune system of the body for the purpose of determining the materials that are encountered in the body. These proteins, produced by the major histocompatibility complex, take the shape of antigens. If we talk about these antigens in the body of human beings, they are represented as human leukocyte antigens. Roitt and Delves (2001) found that these human leukocyte antigens are present on the outer surface of the cells and are presented to the immune system of the body. Here an important point can be noted that when the immune system present in the body feels that the antigen that is attached to any specific cell is dangerous or harmful for the body, the immune system kills that particular cell with which that antigen is attached. This is a very important feature of the immune system while determining the uses of immune system in the body. Clancy (1998) found that it not only recognizes the infections and diseases in the body but also takes appropriate steps for the purpose of treatment of those infections. It is designed in a sense that it allows the immune system to recognize the diseases which are caused due to various types of bacteria and then takes steps to kill those bacteria which arrive in the body of a human being. It also allows the immune system of the body to recognize such cells which are harmful for the body or can affect the systems of the body and then to kill such cells which become harmful for the body due to the presence of injurious antigens attached to them. Sompayrac (2003) found that major histocompatibility complex is extremely diverse in nature and some genes present in the major histocompatibility complex have a lot of alleles that can be said atypical. Diverse nature of major histocompatibility complex is not only a blessing but also a curse. Virella (2001) found that when the MHC will be genetically diverse, it will have an affect on human race which goes stronger due to it particularly in a sense of defensive immunity. But when we say it is curse, it means that it is so because the tissue transplantation between the humans becomes so much difficult. When it comes to the transplantation of blood or tissue from one individual to any other individual, a difficulty can occur and that difficulty is that the human leukocyte antigens of those two individuals may not match. As a consequence, the immune system of that person who will receive the blood or other biological material will take the donor’s blood or biological material as alien and will also attack it. Due to this reason, the transplant rejection occurs. And we talk about negative impacts of the transplantation, we can say that for some cases, this conflict regarding major histocompatibility complex can appear to be very deadly and really harmful for the person who receives the blood or other biological material from some other person. We can also say that major histocompatibility complex is a very large cluster of those genes which are present in the short arm of chromosome 6. Major Histocombatibility complex are also known as those molecules which are present on the surfaces of the cells whose purpose is to recognize the lymphocyte and the presentation of the antigens. It also serves as target for the rejection of transplantation and also control the responses of the immune system through recognizing the self and non self proteins. Defects in the MHC genes Talking about major histocompatibility complex, it should also be mentioned that there are some defects that may arise in certain MHC genes. And these defects may lead to autoimmune disorders. Autoimmune disorders are those disorders in which the body becomes unable to recognize the self-antigens of the body. Some examples of these disorders include diabetes, inflammatory bowel disease and multiple sclerosis. Classification of MHC If we talk about the classification of major histocombatibility complex, we can say that MHC is divided into the following regions based on the groups of genes with those functions that are related to those specific groups of genes. Class I Class II, and Class III While discussing major histocompatibility complex, let’s also discuss these three regions of major histocombatibility complex in detail. Class I region The molecules in the class I region belong to that group of molecules which are known as immunoglobulin supergene family. This family of molecules includes T-cell receptors, immunoglobulin, CD4, CD8 and some other molecules. If we talk about the composition of class I molecules, we can say that these molecules are composed of two polypeptide chains. Now one of those polypeptide chains is encoded by the BCA regions whereas the other polypeptide chain is encoded some where else. Talking about the polypeptides, it is proved by the researches that the length of the MHC encoded polypeptide is approximately 350 amino acids and glycosylated which mean that the molecular weight of those polypeptides is nearly 45kDa. The domains in which the polypeptides are folded are: Alpha-1 Alpha-2, and Alpha-3 B2-microglobulin, which is a 12kDa polypeptide, can not be covalently linked with the alpha-3 domain. A region is present between the alpha-1 domain and alpha-2 domain which is formed in a way that it is bounded by a beta pleated sheet which is at the bottom and two alpha helices which are present on either sides of the region. This region, through non covalent interactions, is capable of binding a very small peptide which is nearly 10 amino acids. This peptide defines the antigen, epitope, which is recognized by the T-cell to which that small peptide is presented. Talking about class-I major histocombatibility complex proteins, they are virtually found in almost all types of the cells and the basic purpose of these proteins is to present fragments of those proteins that are found inside the cells. The killer T-cells checks the peptide antigens. These antigens have got receptors for the proteins of class-I major histocombatibility complex. If we talk about the purpose of this surveillance system, we can say that the main purpose is the identification of the abnormal body cells. These cells include not only those cells which are infected with the viruses but also those cells which are malignant. Relatively unfamiliar peptide antigens are displayed by such cells. Human leukocyte antigens are encoded by the class-I major histocombatibility complex genes. Another main function performed by the class-I MHC genes is the presentation of the antigens. This due to the function of the immune system which finds out and examines what actually is happening in the cells of our body. The immune system is able to examine this while present outside of the cells. Even being at the outer surface, it is able to know what is happening with our cells. Proteins which are present inside the cells of the body are pierced into various small fragments and the MHC proteins display them as peptide antigens on the surface. In this way, the immune system of the body becomes able to differentiate between the dangers level of the self and foreign proteins. Class II region If we discuss class II region of the major histocompatibility complex, we can say that the composition of class-II molecules is also based on two polypeptide chains like the composition of class-I region molecules. But the difference is that in class-II molecules, both of the polypeptide chains are encoded by the D region. Length of these polypeptides in case of class-II molecules is 230 and 240 amino acids. Alpha is 230 amino acids whereas Beta is 240 amino acids. The molecular weights of alpha and beta polypeptides are 33kDa and 28kDa respectively. Two different domains are folded by these polypeptides from which alpha-1 and alpha-2 are alpha polypeptides and beta-1 and beta-2 are beta polypeptides. The region that lies between the alpha-1 and alpha-2 domains is same as class-I molecules. This region is also bounded by two alpha helices on either sides of the region and a beta-pleated sheet is present at the bottom of the region. This region, with the help of non covalent interactions can bind a peptide of approximately 10 amino acids. If we talk about the presence of class-II major histocompatibility complex proteins, researches have shown that these are present on the immune cells like phagocytes that engulf bacteria which is a foreign particle. Sell and Max (2001) found that the purpose of these immune cells is to present the peptide antigens that are derived from the particle that are digested. The helper-cells which contain the receptors for the class-II major histocompatibility complex proteins, receive the antigens from the immune system of the body. The main purpose of this system is to prevent the immune system from attacking the cells. It also controls the immune system and stops it from destroying the cells of the body. Class III region Various components of the complement system are encoded in the class-III major histocombatibility complex proteins. The complement system is a collection of those soluble proteins which are present in the blood that not only targets the foreign cells but also breaks up the membranes. T-cell receptor molecules We can say that T-cell receptor molecule and the B-cell immunoglobulin receptor are similar both structurally and functionally. Alpha and beta are two disulfide linked polypeptide chains which compose the TCR. Just like immunoglobulin, alpha and beta have separate variables and constant domains. Three hyper variable regions are contained by the variable domains which are present for the purpose of recognition of the antigens. It should also be mentioned that the TCR are not able to recognize the antigens without the help. A self appropriate MHC molecule should present the antigenic determinant for this purpose. When that antigen is recognized, a signal of recognition is first generated to the CD3 molecule and the signal is sent towards the T-cell that not only prompts the T-cell activation but also releases the lymphokines. HLA antigens Human leukocyte antigens are the collection of those human genes found on the chromosome 6 that encode the proteins whose main role is to transport the antigens to the surface of the cells from between the cells. Such proteins can also be sometimes known as major histocompatibility complex proteins. Transplant rejection When we talk about the transplant rejection, we can say that transplantation of some tissues or organs between those individuals who are either genetically same or different can be overwhelmed by rejection of transplantation. When the presence of such transplanted tissue membrane of antigens is identified, which is not contained by the host individual, it is termed to be as foreign. And if all other factors like functional state of the donor organ, donor management and interoperate management of the recipient are optimal, then the major cause for the failure of transplantation is said to be the rejection. The autografts and grafts of same individuals like twins are accepted without the medication because they do not have foreign major histocompatibility complex antigens in them. Allografts and Xenografts The major difference between allografts and xenografts is that allografts are generated by the members of those classes who either contain alike or non alike alleles at the major histocompatibility complex loci. Whereas xenografts are generated from the members of such species who are not identical and the major histocompatibility complex can not be identified by the T-cells which results in inactivation of them because of the foreignness of the MHC. Hyper acute graft rejection This rejection occurs straight away upon the transplantation. It may occur because of the preformed antibodies which are either anti MHC antibodies which are formed as a result of blood transfusions or they can be natural antibodies to the blood type antigens, or developed due to the paternal antigens of MHC. Hyper acute rejection can never be reversed and damages the organs. Immediate removal of graft can be the only treatment and by careful cross matching of recipient’s blood and the donor’s blood can prevent the hyper acute graft rejection. Chronic rejection It takes years or months to be manifested clinically and starts at the time of transplantation. For all solid organ allografts, the outcomes of chronic rejection can be same while the biochemical and the clinical signs are organ specific. The cause of the chronic rejection is still not very clear but the researches and the evidences show that immune and the non immune events are responsible for chronic rejection. It can also be said as the long-drawn-out process of declining allograft function. About treatment, we can say that prevention is the best strategy because the only cure for the chronic rejection is retransplantation. Principles of transplantation If we talk about the principles of transplantation, we can say that the immunocompetent host identifies the foreign antigens present on the cells which build up an immune response that causes the rejection. But if the immunocompromised host is grafted with such immunocompetent lymphoid cells that are foreign in nature, the host tissue gets damaged because the immunoreactive T-cells which are in the graft go on to identify the foreign antigens. Graft versus host reaction Histocompatible lymphoid cells are willingly accepted when inserted into an immunocompromised host. Severe damage to the host tissues and the cells occur when the immunocompetent T lymphocytes along with the grafted cells identify the alloantigens. This state of damage to the host cells and tissues is termed as graft versus host disease and the outcomes of such diseases are very harmful for the health and the body. Some common diseases and problems related to graft versus host reaction are erythema, weight loss, joint pains and such fevers which may result in death of the patient. Host versus graft reaction If we talk about the duration of the graft survival, the following order is followed: Xeno- < allo- < iso- = auto- graft. The rejection time depends on the antigenic difference between the recipients and the donors of blood cells and tissues. The major contributors in the transplant rejection are the major histocompatibility complex antigens and up to some extent, the minor histocompatibility complex antigens. It is also proved by the evidences that the rejection regarding minor histocompatibility complex antigens is relatively quicker than the MHC antigen’s rejection. The rejection occurs in such a way that when graft is rejected by the recipient, the second graft and the other followed grafts from the donor will also get rejected in a very less time by the recipient. Current developments regarding MHC As we have discussed major histocompatibility complex and its role in transplantation, we must also talk about those recent developments which are being taking place regarding major histocompatibility complex. So, the current and recent developments in transplantation have a major center of attention on development and improvement of immunosuppressant drugs. These drugs will be much more effective and useful for the patients of various harmful diseases. Such immunosuppressant drugs are being developed which will be steroid free and will be effective for the purpose of strengthening the immune system of the body. The immunosuppressant drugs are being developed using campath-1H which is a humanized monoclonal antibody. The side effects of the steroids will also be foregone in this way. These current developments are really excellent in the field of immunology but the researchers don’t assure the long term effects of these developments as yet. The rate of acute rejection has been lowered down due to the use of calcineurin inhibitors and the allograft survival has also been improved due to this. Some trials regarding the kidney transplantation have also been made which compared the compared the sirolimus-MMF-prednisone with tacrolimus-MMF-prednisone. Some experiments are also being performed on Calcineurin-Inhibitor-Free Immunosuppressant, whose purpose will be to allow the adequate immunosuppression without the nephrotoxity. But the researchers haven’t revealed any sort of positive results regarding those experiments. The researchers are, however, very hopeful of finding such results in the future which will really help them out in discovering appropriate treatments regarding all of the diseases regarding the immune system of the body. References Clancy, J., 1998. Basic concepts in immunology: a student’s survival guide. U.S.A: McGraw-Hills Companies. Eales, L., 2003. Immunology for life scientists. 2nd ed. West Sussex: John Wiley & Sons. Male, D., 2003. Immunology. Milton Keynes: The Open University. Pathak, S. & Palan, U., 2005. Immunology: essential and fundamental. 2nd ed. New Hampshire: Science Publishers. Roitt, I. & Delves, P., 2001. Roitt’s essential immunology. 10th ed. London: Blackwell Science. Sell, S. & Max, E., 2001. Immunology, immunopathology, and immunity. 6th ed. Washington, DC: ASM Press. Sompayrac, L., 2003. How the immune system works. 2nd ed. Massachusetts: Blackwell Science. Virella, G., 2001. Medical immunology. 2nd ed. New York, NY: Marcel Dekker, Inc. Read More