• Causes of Organ Rejection in Kidney Transplantation and a New Proposed Strategy to Improve Survival of the Graft

      Nelson, Mark A.; Abdelhabib, Mohamed; Lybarger, Lonnie P.; Elliot, David A. (The University of Arizona., 2018)
      The kidney is an essential organ that serves a crucial role in preserving homeostasis by filtering blood, regulating fluid levels and maintaining acid/base balance. Any extensive damage to the main unit of the kidney, the nephron, will cause several complications. There are multiple etiologies of kidney injury and they are classified as either acute or chronic. Acute causes are usually easier to treat and the damage resulting from it can be reversed. However, in chronic cases the injury to the kidney might be too severe to the point that renal replacement therapy is recommended. The two options of kidney replacement available are dialysis and kidney transplant. This review will focus on the complications of kidney transplant and ways to increase survival of the graft. The biggest concern with transplantation is rejection of the organ. Rejection usually happens due to immunological response against the graft. That is why pre-operative measures are taken to try to match the donor to the recipient as much as possible. The process involves matching major histocompatibility complex (MHC) and blood antigens. These two molecules are the most important in matching as they play a role in the immune response. The function of MHC in the immune system is to present self and foreign antigens to immune cells. Once immune cells are activated against antigens from the graft, rejection can occur.. Organ rejections involves both the innate and adaptive arms of immunity. Nonetheless, the involvement of adaptive immunity in transplant rejection is better understood. With the adaptive immunity, there are two pathways of rejection, direct and indirect. The direct pathway is where immune cells within the graft present antigens to the recipient’s immune cell to initiate the attack. On the other hand, the indirect pathway is where the recipient’s immune cells recognize antigens from the transplanted organs as foreign and activate the immune system to attack the transplanted organ. Since rejection is mostly an immunological process, the current drug therapies suppress the immune system to increase survival of the graft. These drugs target the activation of immune cells and their proliferation. The new strategy for treatment proposed here is to increase survival of the graft through blockade of MHC-I presentation. The proposed method is to target antigen presentation by MHC-I through a mechanism that is similar to the ICP-47 Herpes Simplex Virus protein that inhibits the function of TAP proteins in antigen presentation. Such a strategy would increase survival of the graft by reducing the effects of the direct pathway of rejection.