Tissue and Transplantation Immunology, Biology tutorial

Introduction:

Transplantation can be stated as procedure or act of transferring cells, tissues or organs from one site to another. Tissue transplantation as the form of medical therapy has grown to be very significant and preferred form of treatment in the range of life threatening clinical conditions like liver, kidney or heart failures. Though, major obstacle to use of tissue transplantation as the routine medical treatment is adaptive immune response. Blood transfusion, which is the earliest and commonest form of tissue transplantation comprises only four major ABO blood types and two Rhesus blood types, therefore matching between individuals to avoid destruction by antibodies is relatively easy.

Immune Responses to Tissue Grafts:

The extent to which immune system responds to the tissue graft will depend on level of genetic differences between graft and the host. The number of terms has been used to categorize graft, according to its origin and possible outcome in host.

Autograft: Transplantation of tissues or organs from same individual like skin. Transplantation is always 100% successful, as they don't elicit rejection.

Syngeneic graft: Transplantation of tissues or organs between genetically identical animals or individuals. Like Autograft, Syngeneic graft undergoes no rejection.

Xenograft: Transplantation of tissues or organs from one species to another. This elicits the maximum immune response.

Allograft: Transplantation of tissues or organs between genetically distinct individuals. This is the most common form of transplantation, and graft is at first accepted but it is then rejected after some days. Degree of rejection is dependent on level of disparity in MHC molecules between donor and recipient. MHC molecules present endogenous and exogenous peptides to T lymphocytes that decide whether peptide-MHC complex is the potentially threatening antigen, thus triggering an immune response. Two mechanisms are involved in recognition of alloantigens in grafted organs, direct recognition; whereby T cells bind directly to donor MHC-peptide complex, causing graft rejection, and Indirect Recognition; is like process whereby T cells become activated in response to the pathogen.

Transplant Tolerance:

Studies have illustrated that although tissue or organ rejection can't be entirely prevented, immunological tolerance can be attained. In the group of liver transplant patients, it was seen that stopping use of immunosuppressive therapy didn't result to rejection of transplant. Many mechanisms have been postulated to describe transplant tolerance; clonal deletion, suppression and anergy. Clonal deletion comprises removal of all T cells which can aggressively respond to self MHC molecules. Despite the reduction in drug treatment for maintenance therapy after transplant, because of the use of modern immunosuppressive induction methods, immunological or transplant tolerance is still a field which needs intense research as most patients are yet to advantage from these methods.

Immunosuppressive Therapy:

There are different immunosuppressive agents utilized in reduction of transplant rejection, and they are grouped according to their mode of actions.

i) CalcineurinBlockers (Ciclosporin and Tacrolimus):

Calcineurin is the protein phosphatase which assists to activate transcription factors essential for initiation of transcription of the number of genes. Ciclosporin and tacrolimus are calcineurin inhibitors which bind to immunophilins within lymphocyte, as a result suppressing activation of T lymphocytes through inhibition of cytokines. Though tacrolimus have similar side effects with ciclosporin, like nephrotoxicity, hypertension, and diabetes, its use is related with the limited number of acute rejection episodes compared to ciclosporin. Ciclosporin is secreted by fungus Tolyplocadiuminflatum, while tacrolimus is the antibiotic derived from soil fungus Streptomycestsukubaensis.

ii) Antiproliferative Agents (Azathioprine and MycophenolateMofetil):

Azathioprine and mycophenolatemofetil are the most usually used in this category, and they act by inhibiting DNA replication through limitation of availability of purines, thus suppressing proliferation of T and B lymphocytes. Both have a similar side effect that is nausea and diarrhea. They are generally used in conjunction with calcineurin blockers, as their normal dose ranges results in suppression of bone marrow.

iii) Corticosteroids:

Corticosteroids are supposed to be cornerstone of immunosuppression, as they have wide range of immunosuppressive activities. Corticosteroids are generally utilized for autoimmune diseases and inflammatory conditions. Several side effects related with corticosteroids have caused many to deviate from its use. Generally commonly used corticosteroids in transplantation are oral prednisolone and intravenous methylprednisolone.

iv) m-TOR Inhibitors (Sirolimus and Everolimus):

Sirolimus and its derivatives are like to tacrolimus in structure, and also bind to immunophilins but they don't inhibit calcineurin but m-TOR. m-TOR, which is mammalian target for rapamycin, regulates gene translation and protein synthesis. Binding of sirolimus to m-TOR inhibits lymphocyte activation. Because of its several side effects, particularly delayed wound healing and delayed graft function, the use of sirolimus is frequently delayed until numerous weeks after transplantation. Sirolimus is derived from soil bacterium Streptomyceshygroscopicus.

v) Antibodies:

Approval of antibodies in therapeutic use in transplantation is merely based on rationale that removal of target cell will diminish the immune response against the allograft. Antibodies react with lymphocyte surface antigens depleting lymphocytes and interfering with immune responses. Common unfavorable effects related with use of antibodies are fevers, chills and headaches.

Immuno-prophylaxis:

Immunoprophylaxis is the branch of immunology which deals with prevention of infectious diseases, through administration of immunological preparations, like vaccines, gamma globulins and hyperimmunesera, so as to make immunity. Immunoprophylaxis has assisted in eradication of several diseases like smallpox, tetanus and poliomyelitis in some parts of the world, and its study is regarded to be significant in prevention and further abolition of infectious and parasitic diseases.

Kinds of Immunization:

Immunization is simply procedure of rendering the individual immune against infectious diseases. Immunization can be passive or active, depending on source of immune response.

i) Passive Immunization:

This involves administration of sensitized lymphoid cells or serum from immune individuals to non-immune individuals, to make immunity. In passive immunity, recipients don't produce antibodies to infectious disease; rather immune response is obtained. Passive immunity can also be natural like transfer of antibodies of the mother to foetus, and lately cure of HIV through bone marrow transplant from immune donors. In most cases, particularly in artificial form of passive immunity, conferred immunity is short-lived, generally 4-6 weeks. Examples of artificial passive immunisations are the injection of serum for the treatment of tetanus or diphtheria, and the administration of gamma globulin to hypogammaglobulin children.

ii) Active Immunization:

This is the treatment which gives immunity to the individual, through administration of the specific antigen, hence stimulating recipient's immune system to generate antibodies against organism. Immunity from this treatment develops slowly, but it is long lasting, at times over the course of complete life of recipient. Active immunization can also be natural, through previous exposure to live pathogen. Active immunisation is also referred to as inoculation or vaccination, as artificial form of active immunisation is through administration of vaccines.

Vaccine:

Vaccine is the immunological preparation which gives immunity to the specific disease. Vaccines are made to look like a pathogen or disease causing microorganism, therefore stimulating immune system to start the response against it. In as much as immune system produces the response against vaccine, response doesn't result in symptoms related with disease. Vaccines assist to prevent diseases like diphtheria, cholera, rabies, poliomyelitis, tetanus and measles. There are different kinds of vaccines, based on strategy to try to decrease risks while retaining ability to produce advantageous immune response.

i) Dead/Killed:

These are vaccines which are made from destruction of previously virulent microbes. Microorganisms are destroyed either through heat (60°C), radiation, chemicals (formalin or phenol) or antibiotics. Killed vaccines most times don't give long lasting immunity, they don't stimulate cytotoxic T cell response, they are safe and can be provided to pregnant women, and they are stable to heat. Examples are polio vaccine, influenza vaccine, cholera vaccine and rabies vaccine.

ii) Live/Attenuated:

These are vaccines made from living microorganisms which have lost their virulent properties, but are still able to produce the immune response when controlled to the recipient. Many of the microorganisms utilized are viruses, whereas some are bacteria and they are known to provoke the durable immune response, therefore making them more preferable for healthy adults to other forms of vaccines. Examples are vaccines developed against measles, viral diseases; rubella and yellow fever and bacterial disease; typhoid fever.

iii) Toxoid:

These vaccines are prepared from detoxification of bacteria toxins, rather than bacteria themselves. The toxins from bacteria are treated with formalin to destroy toxicity and retain antigenic properties. Vaccines prepared from toxins are known to be effective, but not all Toxoid vaccines are prepared from microorganisms. E.g. are vaccines for tetanus and diphtheria.

iv) Subunit:

These are vaccines prepared from part or fragment of the microorganism. Examples are vaccine against Hepatitis B virus that is made up of only of cell surface proteins of virus, the vaccine against Human papillomavirus, made up of mainly of major capsid proteins of the virus.

v) Conjugate:

These are vaccines made by linking polysaccharide outer coat of bacteria with the protein or toxin, so as to allow identification of bacteria by immune response team. As the outer polysaccharide coat on its own generates little or no immune response. E.g. Haemophilusinfluenzae type B virus vaccine.

vi) Experimental:

These are vaccines created from innovations, such as DNA recombination technology. They are also known as synthetic vaccines, and they are very easy to produce and store. Experimental or synthetic vaccines are composed mainly of carbohydrates, antigens or synthetic proteins.

vii) Valence:

At times vaccines are developed to give immunity to more than one microorganism or more than one strain of microorganism, and such are termed polyvalent vaccines. While those that give immunity to just one microorganism is called monovalent vaccine.

In spite of several kinds of vaccines, and success attained so far in eradication of infectious diseases like small pox through administration of vaccines, vaccination doesn't guarantee protection from diseases. Immune response triggered by administration of vaccines, can be affected by different factors like use of steroid by recipient, age of recipient or inability of recipient immune system to trigger production of antibodies to specific antigen.

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