Origin and characteristics of ultraviolet-B radiation-induced suppressor T lymphocytes

CURRENT LITERATURE antibodies by plasmapheresis and suppression of these antibodies by steroids or splenectomy provide a rationale for these treatments in TTR The antibodies are directed against a vWF-cleavage protease that is present in normal plasma. Thus. TTP patients become functionally deficient in this protease, and infusion of fresh frozen plasma (FFP) helps to restore normal levels in the patients' blood. This vWF-cleavage protease cleaves ultrahigh-molecular-weight vWF into smaller multimers. In the absence of normal levels of the protease, ultra-highmolecular weight vWF develops and promotes excessive platelet adhesion and thrombosis. The article by Fuflan et al comes from Bern. Switzerland. The level of vWF cleaving protease in TTP patients' plasma was assessed by incubating patient plasma with normal vWF as a substrate. The extent of cleavage was determined by immunoblotting. To measure the presence of an inhibitor in the patients' plasma, normal plasma was incubated with patient plasma and the effect on vWF cleavage determined. These authors found that all patients with TTP had vWFcleavage protease deficiency. An inhibitor was found in 20 of 24 patients. In contrast, ll of 13 patients with hemolytic uremic syndrome (HUS) had normal levels of the protease. Finally, all six patients with familial TTP had low protease levels without evidence for an lmmunoglobulin G (IgG) inhibitor. The article from HM Tsai is from Dr Lian's laboratory at Montefiore in the Bronx. New York. Their assay for antibodies to the protease is technically simpler. They detected activity of the protease by adding test plasma to purified vWF and then running the product on an acrylamide gel to detect two bands of vWF fragments. The presence of an inhibitor was detected by mixing test plasma with normal plasma and observing the effect on cleavage of purified vWE They found evidence for deficiency of the vWF-cleavage protease in all patients with acute TTR An IgG inhibitor to the vWF-cleavage protease was found in 67% of samples taken during the acufe phase of the illness. These two articles will undoubtedly change the character of our approach to TTE First, they provide the opportunity for a more objective laboratory assay to aid in the diagnosis of this important blood disorder. In particular, the assay may be of great value to distinguish TTP from HUS. In addition, the findings suggest that familial TTP may be treated best by plasma infusion rather than by plasma 9 exchange. Second, the assay may prove helpful in the development of clinical algorithms for the dose of the plasma exchange, for timing of plasma exchange, and for the use of alternative treatments. Third, the unequivocal finding that TTP is at least in part an antibody-mediated disease creates a scientific rationale for the use of newer agents, such as mycophenolate, which are directed against B cells. Finally, the finding of a central role for the vWF-cleaving enzyme provides a clear strategy for isolating and cloning this enzyme. Everyone who has struggled to treat TTP will welcome the day when liters of FFP may be replaced by the combination of anti-B cell therapy plus the injection of the recombinant vWF-cleavage protease. (S.D.)

Origin and characteristics of ultraviolet-B radiationinduced suppressor T lymphocytes. Shreedhar VK, PrideMW, Sun Y, etaI. J Immuno1161:1327-1335, 1998. Ultraviolet B (UV-B) irradiation has dramatic effects on immune cells. UV-B irradiation of platelet concentrates was found in the Trial to Reduce Alloimmunization to Platelets to be

237 as effective as leukoreduction for the prevention of HLA alloimmunization. Extracorp0real UV-B treatment of blood is being actively explored in clinical trials as a means of prevention Of Solid-organ allograft rejection and as a means of treating graft-versus~host disease. Although the mechanism of UV-B light treatment remains incompletely understood, UV-B exerts an immunosuppressive effect and UV-B irradiation interferes with cell surface expression of costimulatory molecules, which are critically important for antigen presentation. This study conducted in mice provides new experimental findings on the potential immunosuppressive mechanism of UV-B irradiation. The experimental model uses low-dose UV-B irradiation to the skin of mice. In previous studies, the authors had found that such skin irradiation impairs the induction of contact hypersensitivity responses to haptens applied to the irradiated skin. This study examined the nature of the lymphocytes found in lymph nodes draining the irradiated areas. Cells that were collected from the draining nodes and transfused into syngeneic mice induce T-suppressor cell activity in the recipients. Such cells also were shown to impair antigen presentation. In this study, congenic mice were used to determine whether the T-suppressor cells were of donor or recipient origin. The investigators found that the T-cell suppression resided in the donor-transfused T cells that had been collected from the lymph nodes of UV-Birradiated animals. Cell lines and clones showed that the cells were CD4+, C D 8 - , T cell receptor alpha/beta positive, major histocompatibility restricted, and specific for the sensitizing hapten originally applied to the skin of the donor animal. Whereas cell lines derived from non-UV-B-irradiated control mice were Thl-like in their pattern of cytokine release, cloned T-suppressor cells derived from the UV-B-irradiated mice exhibited a Th2 pattern of cytokine expression producing IL-10 but no IL-4, or gamma interferon. In vitro, these cells were able to block the function of otherwise normal antigen-presenting cells. Finally, the transfusion of 5 • 104 cloned T-suppressor cells into otherwise untreated recipients suppressed the response of those recipients to contact hypersensitivity haptens applied to their skin. Taken together, these experimental findings suggest that externally applied UV-B irradiation is able to induce a distinct set of regulatory CD4+ T ceils, which collect in the lymph node, draining the affected area of skin. These CD4+ cells behave as T-suppressor cells both in vitro and in vivo. The findings published in this report support clinical observations of the immunosuppressive effect of UV-B light treatment and encourage efforts directed toward adoptive immunotherapy as a means to induce tolerance. (S.D.)

Plasma exchange and tacrolimus-mycophenolate rescue for acute humoral rejection in kidney transplantation. Pascual M, Saidman S, Tolkoff-Rubin N, et at. Transplantation 66:1460-1464, 1998. Most kidney transplant rejection episodes are due to cellular rejection and respond to an increase in the dose of anti-rejectinn medicines (such as cyclosporine or FK506) directed at suppressing host T-cell responses. However, a minority of patients experience humoral-mediated rejection. These patients are identified by graft biopsies that show the presence of neutrophils rather than lymphocytes and by the presence of anti-HLA antibodies in the recipient's serum directed against donor class I