Avenues for immunomodulation and graft protection by gene therapy in transplantation.
Organ transplantation represents the only definitive therapy for many causes of end-organ failure. However, the universal success of this therapy is limited by chronic allograft rejection, the side effects of chronic immunosuppressive therapy, and a severe shortage of donor organs. Presently, the success of solid-organ transplantation depends on the continuous administration of toxic and nonspecific immunosuppressive agents, therapies that present risks for opportunistic infection, malignancy, and a variety of agent-specific side effects. To promote the use of transplantation with limited risk of long-term sequelae, three dominant research challenges emerge: (i) elimination of the need for exogenous immunosuppression by immunological tolerance induction; (ii) prevention of chronic rejection/graft dysfunction; and (iii) expansion of available organs for transplantation. Gene therapy may provide significant advances and solutions in each of these areas. Rejection of the graft in the immediate post-transplant period has been attacked through the transfer of immunomodulatory molecules in addition to tolerance inducing approaches. Chronic graft rejection may be similarly addressed through permanent tolerance induction or alternatively through the introduction of molecules to resist chronic graft damage. Genetic manipulation of stem cells may ultimately produce transgenic animals to serve as tissue donors to overcome the limited donor organ supply. This review will highlight ongoing developments in the translation of gene therapy approaches to the challenges inherent in transplantation.
Moore
Daniel J
DJ
Department of Pediatrics, Vanderbilt University, Nashville, TN, USA.
Markmann
James F
JF
Deng
Shaoping
S
D000818:Animals; D030801:Animals, Genetically Modified; D015316:Genetic Therapy / Q000379:methods*; D023281:Genomics; D006084:Graft Rejection; D006085:Graft Survival; D006801:Humans; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000494:pharmacology; D040901:Proteomics / Q000379:methods; D014180:Transplantation / Q000379:methods*; D014183:Transplantation, Heterologous
D007166:Immunosuppressive Agents