Successful Treatment of Recurrent Rejection in Renal Transplant Patients with Photopheresis ROBERTO DALL’AMICO, LUISA MURER, GIOVANNI MONTINI, BARBARA ANDREETTA, GIOVANNI-FRANCO ZANON, GRAZIELLA ZACCHELLO, Padova, Italy. and FRANCO ZACCHELLO Department of Pediatrics, University of Padua, Abstract. Photopheresis (ECP) is a new form of photochemo- therapy that induces a selective inhibition of the host response to foreign histocompatibility antigens and reverses albograft rejection after organ transplantation. This report describes four adolescent patients with recurrent rejection episodes after renal transplantation, all uncontrolled using standard protocols of immunosuppression (intravenous steroids and OKT3), yet suc- cessfully treated with a 6-mo course of ECP. The ECP treat- ment was performed at weekly intervals during the first month, at 2-wk intervals during the second and third months, and then monthly for another 3 mo. Creatinine clearance improved throughout the treatment in three patients and remained Un- changed in one. All patients had a pre-ECP biopsy with a grade 2 or 3 rejection (Banff) with a diffuse infiltrate CD8, CD14, LFA-1 (166 cells positive/0.048 mm2), and VLA-4 (51 cells positive/0.048 mm2) positive, as well as a tubular expression of HLA-DR (6.2 sections of tubule positive/0.048 mm2), ICAM-l, and VCAM-l (3.1 and 2.9 sections of tubule posi- tive/0.048 mm2). A strong reduction of cell infiltrate and expression of LFA-l (6.6 cells positive/0.048 mm2), VLA-4 (0.7 cells positive/0.048 mm2), HLA-DR (0.2 section of tu- buies positive/0.048 mm2), ICAM- 1 (0.3 section of tubules positive/0.048 mm2), and a disappearance of VCAM- 1 staining were observed in the biopsies performed after 3 mo of ECP. All patients remained rejection-free during ECP, without in- fections or other complications commonly observed with in- creasing doses of standard immunosuppression. The clinical improvement allowed a progressive reduction of oral steroids in three of the four patients treated. (I Am Soc Nephrob 9: 121-127, 1998) Allograft rejection is still one of the major issues in clinical transplantation. Almost 50% of graft failures are caused by rejection, and a large part of recipients of cadaver kidneys have at least one episode of rejection in the first 2 yr after trans- plantation ( 1 ). Several therapeutic and prophylactic measures, including high-dose steroids, antibymphocytic globulin, and a variety of monoclonal antibodies, have been used in the at- tempt to prevent and reverse allograft rejections (2,3). How- ever, some major problems, such as a nonselective mechanism of action, high toxicity that limits the amount of drug often needed for rejection control, and an elevated risk of complica- tions (i.e. , infections and malignancies), are rebated to the administration of the usual immunosuppressive protocols. In addition, long-term albograft survival may be limited by the development of a chronic allograft nephropathy, in which several immunologic and nonimmunologic factors such as drug nephrotoxicity, hypertension, infections, and chronic rejection may play a role. Photopheresis (ECP) is a new form of extraconporeal pho- tochemotherapy currently used for the treatment of cutaneous T cell lymphoma (CTCL) and in some T cell-mediated dis- Received April 2, 1997. Accepted June 3, 1997. Correspondence to Dr. Roberto Dall’Amico, Department of Pediatrics, Uni- versity of Padua, Via Giustiniani 3. 35128 Padova, Italy. 1046-6673/0901-012 1 $030010 Journal of the American Society of Nephrology Copyright 0 1998 by the American Society of Nephrology eases, including pemphigus vulgaris, scieroderma, rheumatoid arthritis, graft-versus-host disease. and systemic bupus ery- thematosus (SLE) (4-9). During ECP, 5 to 7 X l0 peripheral lymphocytes are collected by apheresis and treated in an ex- tracorporeal device with 8-methoxypsoralen (8-MOP) and UVA bight (10, 1 1). Because ECP has been demonstrated to downregulate both neoplastic and autoreactive T cell clones, respectively, in CTCL and autoimmune diseases, it has been hypothesized that it could even modulate abloreactive T cell populations responsible for allograft rejection after organ trans- plantation. After preliminary experiments in animal models showing that its combination with standard immunosuppression pro- longs the survival of transplanted organs. the efficacy of ECP has been demonstrated in cardiac transplant patients with acute rejection (12-14). ECP has also been used in subjects with a high risk of rejection, hypersensitized by previous transplan- tation or multiple pregnancies (15). Prolonged ECP treatment has also been shown to result in a significant reduction of coronary intimal hyperplasia after cardiac transplantation (16). More recently, a prospective multicenter study of 60 cardiac transplant patients showed that prophylactic treatment with ECP reduced the frequency of rejection episodes without in- creasing infection risk (17). Similarly, patients with recurrent rejection after cardiac transplantation experienced a reduction in the number and severity of rejection episodes without any complications after a 6-mo course of ECP ( 1 1). ECP has been recently used in a few cases for the treatment