Transplantation allograft rejection

The literature on chemokines in transplantation has been extensively reviewed in recent years (7-9). In this chapter, we focus on a limited number of chemo-kine receptors where evidence for a functional role has been verified. From the plethora of chemokine receptors, this has been demonstrated for CXCR1/2 in reperfusion injury and for CCR1, CCR5, and CXCR3 during acute and chronic allograft rejection. 

Neuringer IP, Chalermskulrat W, Aris R. Obliterative bronchiolitis or chronic lung allograft rejection a basic science review. J Heart Lung Transplant 2005 24 3-19. 

Panzer U, Reinking RR, Steinmetz OM, et al. CXCR3 and CCR5 positive T-cell recruitment in acute human renal allograft rejection. Transplantation 2004 78 1341-1350. 

For short-term chnical interventions with the aim of protecting the kidney during acute reperfusion or preventing allograft rejection after transplantation, the prerequisite of parenteral administration does not constitute a serious limitation. 

Renal allograft rejection Treatment of acute allograft rejection in renal transplant patients. 

Cardiac/Hepatic allograft rejection Treatment of steroid-resistant acute allograft rejection in cardiac and hepatic transplant patients. 

Eisen HJ, Tuzcu EM, Dorent R, Kobashigawa J, Mancini D, Valantine-von Kaeppler HA et al. Everohmus for the prevention of allograft rejection and vasculopa-thy in cardiac-transplant recipients. N Engl J Med 2003 349(9) 847-58. 

Muromonab-(CD3) Orthoclone OKT3) is a mouse monoclonal antibody that is a purified IgG. It is used for the prevention of acute allograft rejection in kidney and hepatic transplants and as prophylaxis in cardiac transplantation. It is also used to deplete T cells in marrow from donors before bone marrow transplantation. 

Adjunct in prevention of renal allograft rejection PO, IV 2-5 mg/kg/day on day of transplant, then 1-3 mg/kg/day as maintenance dose. 

B. Indications and use Orthoclone OKT3 is indicated for the treatment of acute allograft rejection in renal transplant patients and for the treatment of steroid-resistant acute allograft rejection in cardiac and hepatic transplant patients. 

Murase, N., Kim, D. G., Todo, S., Cramer, D. V., Fung, J. J., and Starzl, T. E. (1990). Suppression of allograft rejection with FK506. 1. Prolonged cardiac and liver survival in rats following short-course therapy. Transplantation 50, 186-189. 

Tacrolimus (previously known as FK506) is a macrolide antibiotic with immunosuppressive properties very similar to cyclosporin. It is more potent than cyclosporin but the side effects are similar. Tacrolimus is a very active immunosuppressive drug both in the prevention and treatment of liver and renal allograft rejection. It is especially valuable for small bowel transplantation. 

Pentostatin is an adenosine deaminase inhibitor primarily used as an antineoplastic agent for lymphoid malignancies, and produces a profound lymphopenia. It is now frequently used for steroid-resistant graft-versus-host disease after allogeneic stem cell transplantation, as well as in preparative regimens prior to those transplants to provide severe immunosuppression to prevent allograft rejection. 

Thistlethwaite, J.R., Cosimi, A.B., Delmonico, F.L., et al. (1984). Evolving use of OKT3 monoclonal antibody for treatment of renal allograft rejection. Transplantation, 38, 695-701. 

Dosage Delaying Onset of Allograft Rejection Fixed dose of 15 mg/kg for 14 days, then every other day for 14 days for a total of 21 doses in 28 days First dose should be administered within 24 hours before or after transplantation Treatment of Rejection 10 mg/kg/d IV for 8-14 days, then every other day up to 21 doses Dose should be infused at least over 4 hours, through a 0.2-1 micron filter... 

Mycophenolic acid (MPA) was isolated from cultures of Penicillium spp. in 1896 and was purified in 1913. Initially the compound was studied for its antifungal and antibacterial effects and later for its antitumor effects. Many years later, its immunosuppressive activities were recognized and after further developmental work, an ester prodrug mycophenolate mofetil was developed, which was approved by the United States Food and Drug Administration for the prevention of acute renal allograft rejection in 1995 and for heart transplant recipients in 1998. Mycophenolate mofetil is a cytotoxic agent now used for immunosuppressive therapy and is the mofetil ester of MPA, which is the active immunosuppressive agent. 

Boratynska M, Banasik M, Patrzalek D, Klinger M. 2006. Conversion from cyclosporine-based immunosuppression to tacrolimus/mycophenolate mofetil in patients with refractory and ongoing acute renal allograft rejection. Ann Transplant. 11 51-56. 

Muromonoab-CD3 is used for the treatment of acute organ transplant rejection. It is effective in preventing graft rejection after kidney, heart or liver transplantation. Muromonoab-CD3 is effective in patients who after acute cardiac or liver allograft rejection do not respond to steroid therapy. It is administered intravenously and with a dose of 5 mg/day, a general concentration range of 400-1500 ng/ml can be achieved. A serum concentration of 600-1150 ng/ml in renal transplant patients produces desirable immunosuppressive effects. The levels of CD3 expression, their production and antibodies to the drug determine its rate of clearance. In the absence of antibodies to muromonoab-CD3, its half-life is about 18 h. 

Cosimi AB, Burton RD, Colvin RB, Goldstein G. 1981. Treatment of cute renal allograft rejection with OKT3 monoclonal antibody. Transplantation. 32 535-539. 

After tissue transplantation, the severity and the period of rejection depend on the tissue type, and this process involves the specificity and memory components of the immune response. Avrion Mitchison in the 1950s observed that allograft immunity could be transferred by the components of the cellular immune response, and antibodies present in the serum that were part of the humoral response were not associated with this process. Future studies delineated the role of T lymphocytes in the allograft rejection process, and the role of both CD4+ and CD8+ cells was established. 

Bishop DK, Shelby J, Eichwald EJ. 1992. Mobilization of T lymphocytes following cardiac transplantation. Evidence that CD4- positive cells are required for cytotoxic T lymphocyte activation, inflammatory endothelial development, graft infiltration and acute allograft rejection. Transplantation. 53 849-857. 

Lattmann T, Hein M, HOrber S, Ortmann J, et al. 2005. Activation of pro-inflammatory and antiinflammatory cytokines in host organs during chronic allograft rejection Role of endothelin receptor signaling. Am J Transplant. 5 1042-1049. 

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