Endomyocardial biopsy findings after photopheresis treatment of cardiac transplant rejection.

Photopheresis is a potential therapy for allograft rejection in which reinfusion of mononuclear cells exposed to ultraviolet-A irradiation after pretreatment with 8-methoxypsoralen may initiate immunosuppressive responses. Endomyocardial biopsies (EMBs) of cardiac transplant recipients with moderate acute rejection (IHSLT grades 2 and 3) treated with photopheresis (7 patients/9 treatments) and followed for six months or more were evaluated and compared with biopsies of patients treated with corticosteroids (7 patients/8 treatments) and followed for a similar time period. The first posttreatment EMB showed improvement in 100% of corticosteroid-treated patients, compared with 56% of photopheresis-treated patients (p < 0.005). Interstitial infiltrates of >90% T-lymphocytes were present in a greater percentage of photopheresis-treated patients than in corticosteroid-treated patients on the first five posttreatment EMBs (p < 0.005) as follows: EMB 1, 90% vs. 25%; EMB 2, 90% vs. 25%; EMB 3, 78% vs. 0%; EMB 4, 56% vs. 0%, EMB 5, 56% vs. 0%. Postphotopheresis EMBs also showed giant cell reaction in 1 patient and extensive band-like infiltrates in 3 patients. Our results suggest that interstitial T-cell infiltrates are more prevalent and persist longer after photopheresis than after corticosteroid treatment of heart allograft rejection. Whether these T-lymphocytes are alloreactive or mediate immunosuppressive signals is unknown. The use of new immunosuppressive therapies may modify endomyocardial biopsy findings, requiring adjustment of the diagnostic criteria for assessing and grading allograft rejection.

Photopheresis versus corticosteroids in the therapy of heart transplant rejection. Preliminary clinical report.

BACKGROUND: Photopheresis is a technique in which reinfusion of mononuclear cells exposed to UV-A light ex vivo after in vivo treatment with 8-methoxypsoralen initiates host-immunosuppressive responses. METHODS AND RESULTS: To determine if photopheresis safely reverses International Society for Heart and Lung Transplantation (ISHLT) rejection grades 2, 3A, and 3B without hemodynamic compromise, 16 heart transplant patients with ISHLT rejection grades 2, 3A, and 3B were randomized to photopheresis or corticosteroid therapy. The average number of mononuclear cells treated with each photopheresis procedure was 9.8 +/- 9.1 x 10(9) (mean +/- SD). Photopheresis and corticosteroids reversed eight of nine and seven of seven episodes of rejection, respectively. The median time from initiation of treatment to rejection reversal was 25 days (range, 6-67 days) in the photopheresis group and 17 days (range, 8-33 days) in the corticosteroid group. Hemodynamics were normal before either treatment and did not change after reversal of rejection. No adverse reactions occurred with photopheresis, and all patients in either treatment group are alive. CONCLUSIONS: These preliminary, short-term results in prospectively randomized patients indicate that photopheresis may be as effective as corticosteroids for treating ISHLT rejection grades 2, 3A, and 3B. The apparently low toxicity and potential efficacy of photopheresis warrant further analysis of its role in the prevention and treatment of heart transplant rejection.

Successful treatment of heart transplant rejection with photopheresis.

Photopheresis is a potential therapy for rejection in which reinfusion of mononuclear cells exposed to ultraviolet-A light ex vivo, after treatment with 8-methoxypsoralen in vivo, initiates host immune responses that specifically inhibit the cytotoxicity of the photomodulated mononuclear cells. Between May 1990 and January 1991, 7 heart transplant (HT) patients (age 42.2 +/- 16.7 [mean +/- SD] years) on triple immunosuppression (cyclosporine, corticosteroids, and azathioprine) had 9 episodes of non-hemodynamically compromising moderate rejection that were treated with photopheresis. These episodes of rejection occurred at an average of 114.4 +/- 180.5 (range 8-575) days after HT. After oral administration the mean serum level of 8-methoxypsoralen achieved was 129.0 +/- 72.4 ng/ml. An average of 10.4 +/- 9.6 x 10(9) mononuclear cells were treated with each photopheresis procedure. Photopheresis was performed twice when less than 5 x 10(9) mononuclear cells had been treated with the first procedure. Of 9 rejection episodes treated with photopheresis, 5 required 1 procedure and 4 required 2 procedures. Photopheresis was used to treat a single episode of rejection in 5 pts. and 2 separate rejection episodes in 2 additional pts. Eight of 9 episodes of rejection were successfully reversed by photopheresis as assessed by endomyocardial biopsy (EMB) performed 7 days after treatment. Immunohistochemical analysis of EMB samples revealed that postphotopheresis cell counts for T cells, B cells, and macrophages were reduced compared to pretreatment values and correlated with the histopathologic resolution of rejection. Hemodynamics were normal prephotopheresis and remained unchanged at the time when the postphotopheresis EMB showed no evidence rejection No adverse effects have been observed with photopheresis. Over a follow-up period of 5.3 +/- 4.0 months, rejection and infection rates/pt./follow-up months were 0.3 +/- 0.4 and 0.04 +/- 0.07, respectively. The preliminary, short term results of this pilot study indicate that photopheresis may be efficacious in the treatment of moderate rejection in hemodynamically stable HT patients and thus may be an alternative to corticosteroid pulses.

Long-term follow-up of heart transplant recipients treated with murine antihuman mature T cell monoclonal antibody (OKT3): the Loyola experience.

We describe the long-term follow-up of 25 patients treated with murine antihuman mature T cell (OKT3) monoclonal antibody at Loyola University Medical Center. After OKT3 rescue therapy, 12 patients were monitored for 16.5 +/- 6.5 months. Twenty-two moderate and three severe rejection episodes occurred 11 to 469 days (166.8 +/- 126.0) after OKT3 therapy in nine of 12 patients. During the follow-up period three patients died, and one required retransplantation because of recurrent rejection. The coronary arteries of three failed allografts had severe intimal thickening and infiltration with lymphocytes. Thirteen patients received OKT3 for prophylactic immunosuppression, and their course was compared to that of 13 patients who underwent transplantation during the same period but were given prophylactic horse antihuman thymocyte globulins (HATG). There were no differences between the two drugs with respect to long-term incidence and severity of rejection and infection, cardiac allograft function, and survival. Our results indicate that, despite successful reversal with OKT3, heart transplant recipients with refractory rejection remain plagued by recurrent rejection. Cardiac allografts in recipients who die as a result of recurrent rejection show evidence of immune-mediated vasculitis, which results in severe and diffuse coronary luminal narrowing. OKT3 and HATG appear to be equally effective for rejection prophylaxis.