Background

Transplantation refers to the implantation of cells, tissues, or organs from one individual to another. My focus is in organ transplantation in cases where the immune response is elicited and the organ rejection rate is high viz; allograft/allogenic graft (transfer between two genetically distinct members of the same species, human > human) and xenograft/xenogenic graft (transfer between two individuals of two different species, pig > human). In cases where the organ rejection rate is high, the primary cause is due to dissimilar histocompatibility antigens which elicit an immune response causing graft rejection. The ultimate goal is to develop a medical procedure wherein we take an incompatible organ (graft), and modify it so that the antigens on the graft and host are identical (causing no immune response); so that the graft is accepted by the host due to the presence of similar type of antigens. Now, let us delve into the underlying science of transplantation immunology and the role of antigens in this regard. Introduction of allograft or xenograft organ by transplantation is recognized by the human body as a foreign substance. The human body reacts by invoking an immune response- the aim of the immune response is to inactivate, destroy, and eliminate the foreign body. There are two types of immune responses; the humoral/antibody response which involves B lymphocytes (B cells) in which antibodies are produced in the blood plasma, and the cell-mediated response which involves activated T lymphocytes (T cells) playing a major role and they are designed to destroy the foreign substance. The rejection of the graft is due to an immunological reaction- The graft tissue releases antigen into the recipient, the immune system of the recipient recognizes the antigen as non-self and elicits an immune response which rejects the graft. Graft rejection is brought about by cell-mediated immunity/response. In cell-mediated immunity/response, T cells, macrophages, and natural killer (nk) cells are involved. When the antigen enters the body, it is recognized by either T lymphocytes i.e. cytotoxic T cells (Tc cells) or macrophages. If recognized by Tc cells (limited antigen recognition ability), they bind to the antigen and kill it by releasing lysosomal enzymes. The Tc cells recognize the processed antigen with HLA (human leukocyte antigen; a class I MHC molecule- MHC or major histocompatibility complex refers to a cluster of genes that control the production of antigens and are responsible for immune response, transplantation antigens, and proteins of the complement system) along with the processed antigen, the Tc receptor binds to the antigen, the activated Tc cell releases a pore forming protein celled perforin which in the presence of Ca++ binds to the membrane of the antigen and forms transmembrane perforin channels. Through these channels, The Tc cell releases lysosomal enzymes into the antigenic/target cell which fragments the antigen and kills it. The presentation of antigens by macrophages appears to be very specific, and in the case to Tc cells; should bear the class I MHC antigen. The class I MHC of man is called HLA and is responsible for graft rejection; it is located on the short arm of chromosome 6 in the A,B,C gene loci. Note: Some of the sensitized T cells function as memory cells in cell-mediated immunity/response; they survive throughout life and play a role in second injection/introduction of a previous antigen. Memory cells are responsible for the quick and enhanced immunological reaction during secondary immune response, and they bring about immunological memory. Immunological memory is the basic principle of vaccination. If recognized by macrophages, it processes and presents the antigen along with Ia protein on its surface to Tc or Th cells. Some macrophages on their surface contain HLA. The Th cell has a Ia receptor; it recognizes the antigen with the Ia protein present on the surface of the macrophage, causing an interaction between Th and macrophage which stimulates the macrophage to release a soluble factor called interleukin-I (lymphocyte activating factor). The antigen-Ia molecule complex and interleukin-I activate Th which releases a soluble factor called lymphokine which activates the macrophages to accumulate around the antigen and dispose it by phagocytosis. In the case of graft rejection, the mechanism of rejection occurs in two ways- the HLA (human leukocyte antigen) of the graft stimulates the Th cells, which in turn stimulates the Tc cells. As mentioned above, the Tc cells kill the graft cells directly by the cytotoxic/lysosomal method, and the Th cells release lymphokines which eventually results in phagocytosis. The immune reaction leading to graft rejection may be of two types- host versus graft reaction, and graft versus host reaction.

• Host versus graft reaction

• Graft versus host reaction

All the nucleated cells of the human body contain on their surface a set of antigens called human leukocyte antigens (HLA) or transplantation antigens or histocompatible antigens. These antigens play a significant role in the acceptance or rejection of a graft. When an organ or tissue obtained from a donor is accepted following a graft by a recipient, the cells of the two are histocompatible. This means that transplantation is successful between histocompatible donors and recipients, and the transplantation antigens OF THE GRAFT AND HOST ARE IDENTICAL and do not elicit an immune response. Before transplantation, the tissues are typed for histocompatibility (HLA typing) by using lymphocytes and mixing with anti-HLAAB8 antiserum and complement (large, thermolabile enzymatic proteins found in blood serum and body fluids activated by antigen-antibody complexes and facilitate lysis, phagocytosis..etc). If the lymphocytes die, there is no histocompatibility between the donor and the recipient (dead cell pick up typan blue stain); if the lymphocytes survive, there is histocompatibilty between the donor and the recipient and the graft will survive. By obtaining the best possible match between the donor and recipient (lymphocyte survival rate), the grafting procedure becomes far less hazardous and there is success in organ transplantation of kidney, heart..etc and tissues like skin, bone marrow..etc.

Mr. Somesh R. Doddi