BIOLOGY OF TISSUE TRANSPLANTATION / GRAFTING

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Transplantation is simply the medical procedure of replacing an abnormal or diseased/damaged cell, tissue or organ by a functional and normal one. Normal tissues, cells or organs are usually obtained from donors (living or deceased) and transplanted to the recipient hosts in cases of medical emergencies and need. This surgical and immunological procedure is life-saving in the sense that there is a restoration of the normal physiological function of a damaged organ or tissue in the recipient host(s). In transplantation immunology, the transferred organ or tissue (i.e., the one emanating from the donor host) can also be referred to as graft. Grafts/grafting and transplantation can sometimes be used synonymously too. Cells or tissues can be grafted from one part of the body to another part and also between two different or related animal or human hosts. Blood cells, cornea, heart, bone marrow cells, kidney, and skin cells are some examples of the types of tissues, cells or organs that are often transplanted in humans.

Despite their clinical significance especially in the restoration or re-establishment of the normal functioning of a given organ or tissue; transplantation is associated with some untoward effects which sometimes thwart its purpose in the recipient host. Typical amongst these setbacks of transplantation or grafting is tissue or organ rejection. The rejection of a grafted or transplanted tissue or organ by the recipient host is one of the major problems of organ transplants. As aforementioned, every individual (except in identical twins) have a unique human leukocyte antigen (HLA) or major histocompatibility complex (MHC) molecule that lines their cell membranes. The uniqueness of the HLA/MHC molecules causes the rejection of grafted tissue, cells or organs because the body of the recipient host sees these grafted tissues or organs as foreign, and thus mounts an immunological response against them.

Cellular and antibody-mediated immune responses as facilitated by the T lymphocytes and antibodies respectively are immediately stimulated to mount an attack against the grafted tissue or organ; and this is mostly experienced in cases where tissues, cells or organs are grafted between unrelated hosts. Tissue or organ rejection in transplants is less-likely in individuals that are closely or genetically-related. Transplants between identical twins also have a lesser possibility of undergoing rejection. When the HLA/MHC molecules of the donors and the recipients are not identical, the recipient’s cellular and/or humoural immune responses sees the incoming tissue, cell or organ as foreign and thus the recipient’s immune system mounts an immunological attack against the grafted tissue, thereby leading to its rejection. HLA/MHC typing prior to cell/tissue/organ transplant in the laboratory is important and should always be undertaken prior to any transplanting/grafting in order to identify the genetic-relatedness of the donor and recipient cells (i.e., the closest HLA/MHC match between the donor and recipient hosts). This practice has helped to save a variety of transplantation procedures in humans and animals alike even though some patients have to wait longer until a suitable match and willing donor is identified. Recipients and donor should have similar HLA/MHC molecules for transplantation to be successful.

To prevent rejection clinically, some medical procedures or techniques are also available to ensure tolerance of the grafted cells/tissues/organs by the host’s body. Livelong immunosuppressive drugs for example, have been used clinically to prevent the rejection of grafts in recipient hosts; and these measures help to ensure the survivability of the grafted tissues in the recipient host. These immunosuppressive drugs and/or anti-inflammatory drugs used during transplantation (e.g., cyclosporine, corticosteroids, antiserums and antimetabolites to mention a few) help to induce the tolerance of the recipient’s body to the grafted cell/tissue/organ. However, these immunosuppressive or anti-inflammatory drugs helps to calm the recipient’s immune system and thus make it to be more tolerant to the grafted tissues, cells or organs – which it sees as foreign or non-self molecules.

In an immunological tolerant state especially when immunosuppressive drugs are used during transplantation as aforementioned to prevent possible rejection of the grafted tissues or organs, the immune system of the recipient organism is taught to become amenable and unresponsive to alloantigens and the grafted tissues, thereby extending the viability of the graft. The rejection of a grafted tissue, cell or organ generally leads to a clinical condition known as graft versus host disease (GVHD). Graft versus host disease (GVHD) or reaction is a medical condition that develops when cells from the grafted tissue or organs (i.e., from the donor host) react against or with the recipient’s own tissues leading to an immunological response that facilitates the rejection of the transplanted cell/tissue/organ. GVHD (which usually occur in bone marrow and liver transplants) is mainly mediated by the cell-mediated immunity and the T cells play a critical role in this immunological reaction. The T cells from the graft or transplant recognizes the alloantigens of the host cells i.e., their MHC molecules as foreign and thus mounts an immunological response against it.

Alloantigens are unique antigenic molecules found on the surfaces of host cells and they vary among the individual members of a given species, humans and animals alike. They are antigens that are found in another member of the host’s species; and these antigens are capable of provoking an immunological response in the host. Alloantigens are important decisive-factors to be considered in transplantation and even in blood transfusions since they are unique self-molecules of the host and differ amongst members of the same species. GVHD is a Type IV hypersensitivity reaction; and it occurs mainly in immunocompromised individuals receiving immunocompetent cells. The tissues of the recipient host are attacked in a GVHD condition by the transfused cells of the donor host few days later or after the transplantation procedure. The mechanism of graft rejection in human or animal hosts is usually characterized by two stages viz: the sensitization stage and the effector stage; and both of these phases of tissue rejection are responsible for the rejection of grafted cells or tissues or organs.

Sensitization stage is the first phase in the rejection of transplanted tissues, cells or organs. In this stageof graft rejection, the immune system of the recipient host becomes sensitized by the grafted tissues (in response to allergens in particular) and this stimulates an immunological response especially the T cells to proliferate into effector molecules which mounts a rejection reaction at a later stage. In the effector stage, a variety of immunological mechanisms including but are not limited to, ADCC, TDTHreactionsandcytolytic activities mediated by T cytotoxic (TC) cells are involved. At this stage (i.e., the effector stage of tissue rejection), activated macrophages and T lymphocytes sensitized at the sensitization stage migrate in a rapid fashion to the site of graft; and this mechanism facilitates the outright rejection of the grafted tissues, cells or organs. During the effector stage of graft rejection, chemokines and cytokines in particular including the interleukins, TNFs and interferons play a critical role in facilitating graft rejection and this is because these molecules help to stimulate the proliferation of cytotoxic T cells – which eventually carryout targeted killing of cells associated with the grafted tissue or organ.

Graft rejection can be acute, chronic or hyperacute in nature depending on the level of immune response mounted on the grafted tissue or organ. In acute rejection, there is an infiltration of lymphocytes and monocytes to the graft and this rejection which occurs few days after transplantation is mainly mediated by T cells. Chronic rejection occurs months or years after grafting and it is mainly mediated by antibodies, cytokines and complements. In hyperacute rejection, grafted tissues or organs are rejected immediately (i.e., few minutes or hours) after transplantation; and this type of rejection is mainly mediated by preformed antibodies in the recipient host which recognizes alloantigens or antigens of the donor host. There are four major types of graft or tissue/organ transplantation that can occur in humans or animals and they include: autograft, isograft, allograft and xenograft (Table  1).

Table 1. Types of grafting or transplantation  

Type of graftClinical connotationLevel of rejection
AutograftThis is a self-tissue graft in which tissues obtained from a given individual or donor is transplanted back into the same donor. Autograft is usually used in cases where tissues are grafted from one location of the body to another location on the same host. Typical example is the grafting of skin tissues from the thigh to restore the normal functioning of another part of the skin (e.g., face or arms) that is severely damaged due to burns or accidents. This type of grafting can also be called autologous grafting or autologous transplant because the graft was taken from one location in the donor and returned to the same donor at a different body site. Autograft is often employed in plastic surgery in burnt individuals and also in cardiac bypass surgical procedures in which blood vessels from the legs are grafted to the heart region in the same individual.   Low  
IsograftIsograft is a type of grafting or transplantation in which tissues, cells or organs are grafted between individuals that are genetically identical (e.g., identical twins). This type of graft can also be called isogeneic graft or isogeneic grafting; and it can also be used to transfer tissues between clones of an organism or inbred animals. Low
AllograftAllograft is a type of graft in which tissues are grafted between members of the same species that are genetically different. This is the type of graft that is mostly obtainable in humans in which tissues, cells or organs are grafted from the donor host to the recipient host. Allograft can also be called homograft, and it is a transplant that occurs between allogenic individuals i.e., members of the same species who have different genetic makeup. High
XenograftXenograft is a tissue transplant in which cells or tissue is taken from an individual of one species and inserted or grafted into another individual of a different species (e.g., graft between man and monkey or vice versa). This type of graft can also be called heterograft. Xenograft occurs in xenogenic individuals i.e., individuals of different species that have different genetic lineage. Rejection of grafted tissues or organs is greatest in xenografts because of the presence of high cross-reacting immunoglobulins from both the donor and recipients which induce a hyperacute rejection upon transplant.    Very High

The greatest genetic discrepancy in tissue grafting is mostly experiencedinxenografts; and this is due to the high level of genetic un-relatedness that exists between the donors and the recipient hosts. Autograft and isograft are often the most accepted transplantations and they experience little or no rejection in some cases. Allografts also express tissue rejection like the xenografts because of the dissimilarity that exist between the cells of the donor organism and that of the recipient host. However, immunosuppressive drugs and/or anti-inflammatory drugs (e.g., cyclosporine, corticosteroids, antiserums and antimetabolites) can be used clinically during allograft transplantation to reduce or mitigate rejection by inducing some levels of immunological tolerance in the recipient’s body to the grafted cell/tissue/organ. The level of immunological response to a graft is usually dependent on the type of tissue/organ transplantation or grafting taking place. The classification of graft into these four categories (i.e., autograft, isograft, allograft and xenograft) is also based on the genetic relatedness or relationship that exists between the donor host and the recipient host.                                

Further reading

William E.P (2003). Fundamental Immunology. 5th edition. Lippincott Williams and Wilkins Publishers, USA.

Stevens, Christine Dorresteyn (2010). Clinical immunology and serology. Third edition. F.A. Davis Company, Philadelphia.

Silverstein A.M (1999). The history of immunology. In Paul, WE (ed): Fundamental Immunology, 4th edition. Lippincott Williams and Wilkins, Philadelphia, USA.

Paul W.E (2014). Fundamental Immunology. Seventh edition. Lippincott Williams and Wilkins, USA.

Male D, Brostoff J, Roth D.B and Roitt I (2014). Immunology. Eight edition. Elsevier Saunders, USA.

Levinson W (2010). Review of Medical Microbiology and Immunology. Twelfth edition. The McGraw-Hill Companies, USA.

Berzofsky J.A and Berkower J.J (1999). Immunogenicity and antigen structure. In Fundamental Immunology, 4th edition., W.E. Paul, ed., Lippincott-Raven, Philadelphia. 

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