Photopheresis for the prevention and treatment of transplant rejection.

Current immunosuppressive protocols impair immune function in a nonspecific fashion and may result in opportunistic infections, malignancy, and direct side effects of the drugs. Moreover, there remains a significant morbidity/mortality from rejection, both acute and chronic forms, representing organ-specific underimmunosuppression. The inability to discriminate between clones of pathogenic and benign T cells and the problem with chronic B-cell-related humoral immunity has lead to new therapies. Based on prior work in rat autoimmune encephalitis and murine lupus models, a study was performed in which CBA/j mouse donor skin was grafted onto Balb/c mice. Upon skin graft rejection, the spleen from the transplanted mouse was removed and splenic lymphocytes were treated with 8-methoxypsoralen (8MOP) and UVA. Naive Balb/c mice treated with the photoinactivated CBA/j spleen cells demonstrated decreased MLC and cytotoxicity to CBA/j antigens. In vivo, the treated mice had longer survival of CBA/j grafts yet retained the ability to respond to third-party grafts. Studies on primate cardiac xenografting were performed in a heterotopic cynomologous monkey to baboon model, using a cydosporine and steroid regimen with addition of prophylactic photopheresis. The photopheresis group had increased donor-specific immunosuppression, as evidenced by inhibited MLC and decreased lymphocytotoxic antibodies to the donor, with prolonged xenograft survival. In addition, resolution of an acute rejection episode was seen using increased photopheresis without augmentation in conventional immunosuppression. Based on the murine and primate work and the experience and safety seen in cutaneous T-cell lymphoma, human cardiac transplantation trials were begun. In one study, high-risk patients with elevated levels of nondonor-specific anti-HLA antibody (PRA) were treated with adjuvant photopheresis. Decrease in PRA and a relatively low incidence of rejection was seen. In a subsequent study, a single photopheresis treatment was compared with corticosteroids in the treatment of hemodynamically stable cardiac rejection. Photopheresis alone was capable of reversing acute rejection, although the success and time to complete resolution was inferior to steroids. Based on the observation that there is an association between elevated PRA and the development of transplant atherosclerosis, a study was performed to determine whether the addition of monthly photopheresis to triple drug therapy results in a decrease in PRA and atherosclerosis. An early reduction in PRA was seen. Of greater clinical importance was the finding of a significantly decreased coronary artery intimal thickness (by intravascular ultrasound) at up to two-year followup. Based on these studies, an international multicenter trial was performed to investigate the impact of prophylactic therapy on the incidence of acute rejection and infection in cardiac transplant patients. Sixty primary cardiac recipients were randomized to receive either triple drug therapy alone or in conjunction with photopheresis. The photopheresis group received two sequential day photopheresis treatment cycles: 5 cycles in the first postoperative month, 4 in the next 2 months, and 3 in postoperative months 4‐6. The photopheresis group had a 2.13 times greater likelihood of being rejection free versus the standard group. The standard group had a 2.64 times greater relative risk of multiple rejections compared with the photopheresis group.