Maritza I. Perez

Treatment of erythrodermic cutaneous T-cell lymphoma with extracorporeal photochemotherapy

BACKGROUND This original cohort of patients with erythrodermic cutaneous T-cell lymphoma (CTCL) was reported to have clinical improvement with photopheresis during the 12 months of the original study. No long-term follow-up data have been available to examine the impact of this therapy on the disease. OBJECTIVE Our purpose was to provide long-term follow-up on the original 29 erythrodermic CTCL patients treated with photopheresis and to compare these results with historical controls. METHODS Files of patients from the original photopheresis study centers were reviewed and their current status was documented. RESULTS The median survival of the treated patients was 60.33 months from the date of diagnosis and 47.9 months from the date of the start of photopheresis therapy. A complete remission has been maintained in four of the six patients who achieved complete responses in the original study. The best responses were seen in patients with a lower CD4/CD8 ratio in the peripheral blood at the start of therapy. CONCLUSION Photopheresis can influence the natural history of erythrodermic CTCL by inducing remissions and prolonging survival with minimal toxicity.

Cutaneous manifestations of diabetes mellitus

Diabetes mellitus (DM) is a heterogeneous group of disorders characterized by a high serum glucose level and by disturbances of carbohydrate and lipid metabolism. It is estimated that 11 million persons in the United States have DM, 90% of whom have non-insulin-dependent DM. At least 30% of persons with diabetes have some type of cutaneous involvement during the course of their chronic disease. This review classifies the cutaneous findings in DM into four categories: (1) skin diseases with strong to weak association with DM; (2) cutaneous infections; (3) cutaneous manifestations of diabetic complications; and (4) skin reactions to diabetic treatment. Each of these categories is reviewed as well as the pathophysiology of the normal and diabetic basement membrane for a better understanding of the cutaneous manifestations of DM.

Inhibition of antiskin allograft immunity by infusions with syngeneic photoinactivated effector lymphocytes

Induction of tolerance for skin allotransplantation requires selective suppression of the host response to foreign histocompatibility antigens. This report describes a new approach that employs pretreatment of effector cells with 8-methoxy-psoralen (8-MOP) and ultraviolet A light (UVA) to render the effector cells of graft rejection immunogenic for the syngeneic recipient. Reinfusion of photodamaged cells resulted in an immunosuppressive host response that permitted prolonged retention of histoincompatible skin grafts and specifically inhibited in vitro and in vivo responses that correlate with allograft rejection. Eight days after BALB/c mice received CBA/j skin grafts, their splenocytes served as a source of alloreactive effector cells. The splenocytes were treated with 100 ng/ml 8-MOP and 1 J/cm2 UVA before reinfusion into naive BALB/c recipients. Recipient mice were tested for tolerance to alloantigens in mixed leukocyte culture (MLC), cytotoxicity (CTL), delayed type hypersensitivity assays (DTH), and challenge with a fresh CBA/j graft. Splenocytes from BALB/c recipients of photoinactivated splenocytes containing the effector cells of CBA/j alloantigen rejection proliferated poorly in MLC and generated lower cytotoxic T cell responses to CBA/j alloantigens in comparison with sensitized and naive controls. Splenocytes from these hyporesponsive mice suppressed the MLC and CTL response to alloantigen from sensitized and naive BALB/c mice. In vivo the DTH response was specifically suppressed to the relevant alloantigen in comparison with controls. Moreover, BALB/c mice treated in this fashion retained a CBA/j skin graft for up to 42 d posttransplantation without visual evidence of rejection. These results indicate that the in vivo and in vitro response to alloantigen can be attenuated by pretreating the host with photoinactivated splenocytes containing the effector cells of alloantigen rejection.

Correlations of unique clinical, immunotypic, and histologic findings in cutaneous gamma/delta T-cell lymphoma

Cutaneous T-cell lymphoma is a malignancy of T cells that express a clone-specific heterodimer T-cell receptor for antigen. The second recognized case of an epidermotropic malignancy of T-cells expressing gamma/delta T-cell receptor-expressing cells is reported. The immunophenotype of the malignant T-cells was CD3+, CD2+, CD7+, gamma/delta T-cell receptor+, CD4-, CD8-, and alpha/beta T-cell receptor-. The clinical features were remarkable for extreme epidermotropism with a scant dermal lymphomatous infiltrate. Profound keratinocyte necrosis occurred in areas of malignant skin infiltrates. Despite cutaneous lesions covering more than 50% of the skin surface of the patient, no adenopathy or splenomegaly was detected. The intense epidermotropism of this patients gamma/delta T-cell receptor-expressing cells and the putative cytolytic properties of CD4- CD8- gamma/delta contributed to the destruction of epidermis. Remission was induced with a combination of electron beam and extracorporeal photochemotherapy.

INHIBITION OF ANTI-SKIN ALLOGRAFT IMMUNITY INDUCED BY INFUSIONS WITH PHOTOINACTIVATED EFFECTOR T LYMPHOCYTES : THE CONGENIC MODEL

We have previously reported the capacity to produce donor-specific tolerance to alloantigens by intravenous exposure to pretreated antidonor T cells. The current study has refined this system by using congenic mice differing only at the H-2 major histocompatibility complex genetic loci. Twelve days after B10 mice received MHC-incompatible B10.D2 skin grafts, their splenocytes that included an expanded population of cells mediating rejection were treated with 100 ng/ml 8-methoxypsoralen (8-MOP) photoactivated by 1 J/cm2 of ultraviolet A prior to infusion into naive B10 recipients. Whereas 8-MOP itself is biologically inert, photoactivated 8-MOP crosslinks DNA by covalently binding to pyrimidine bases. Recipient B10 mice were tested for tolerance to B10.D2 alloantigens in mixed leukocyte culture (MLC), cytotoxicity (CTL), and to in vivo delayed type hypersensitivity assays and challenged with a fresh B10.D2 graft. In vivo, the DTH response of the pretreated B10 mice was specifically suppressed to the relevant alloantigen, correlating with retention of B10.D2 skin grafts for up to 22 days postengraftment without visual evidence of rejection, in comparison to control complete rejection of the skin graft in less than 12 days. In vitro, splenocytes from B10 recipients of pretreated syngeneic splenocytes containing large numbers of B10 anti-B10.D2 T cells proliferated less in MLC and generated lower cytotoxic T cell responses to B10.D2 alloantigens than did controls and suppressed the B10 MLC and CTL responses to B10.D2 alloantigen. These results reveal that, in a highly defined congenic transplantation system, infusions of photoinactivated effector cells resulted in selective inhibition of the in vivo responses that correlated with allograft rejection and permitted prolonged retention of histoincompatible skin grafts. This approach may have significant practical applicability for treatment of human disorders caused by aberrant T cells.

DNA ASSOCIATED WITH THE CELL MEMBRANE IS INVOLVED IN THE INHIBITION OF THE SKIN REJECTION RESPONSE INDUCED BY INFUSIONS OF PHOTODAMAGED ALLOREACTIVE CELLS THAT MEDIATE REJECTION OF SKIN ALLOGRAFT

Abstract

Acral persistent papular mucinosis

blood coagulation factor Xa in the tick Ornithodoros moubata. This factor, tick anticoagulant peptide, is a serine protease inhibitor, specific to factor Xa. It might be the cause of the response in our patients who had been bitten by a similar tick species. Galun and Ben-Chetrit lo prophylactically treated 13 persons with cave tick bites with tetracycline, 1 gin/day, for 3 to 5 days; none of them had symptoms of tick-borne relapsing fever. They suggested that a short-term, low-dose course of tetracycline might prevent the disease. Our treatment with tetracycline was not followed by relapsing fever.

Antigen-specific tolerance induced by autoimmunization with photoinactivated syngeneic effector cells.

Development of a protocol that could invoke specific suppression of an undesired immune response, while sparing normal immune competence, would be of great clinical value. This report demonstrates that multiple infusions of splenocytes sensitized in vivo to sheep red blood cells (SRBC) and photoinactivated in vitro with 8-methoxypsoralen and ultraviolet A light can render a syngeneic recipient selectively unresponsive to subsequent challenge with this antigen. Mice treated in this fashion did not develop a T cell-mediated delayed type hypersensitivity (DTH) reaction to SRBC. In contrast, control mice exposed to nonimmune splenocytes pretreated in an identical manner developed a normal DTH response to SRBC, thereby demonstrating that drug and light in the absence of effector T cells were not suppressive. Inhibition of the DTH response was antigen specific, since animals rendered unresponsive to SRBC developed a normal DTH response to chicken red blood cells. Cell transfer experiments demonstrated that unprimed recipients of splenocytes from mice rendered unresponsive to SRBC could not mount a DTH reaction when challenged. Moreover, this procedure can also suppress established immunity to that antigen. The use of photoinactivated syngeneic antigen-reactive effector cells as immunosuppression agents suggests that this method may be clinically useful in inhibiting pathogenic antigen-specific immunologic reactions.

Suppression of anti-skin-allograft response by photodamaged effector cells : the modulating effects of prednisolone and cyclophosphamide

Using a murine model of skin allotransplantation, we have demonstrated previously that inhibition of specific response to alloantigen is inducible by immunization of the host with intravenously administered photoinactivated antigraft effector T cells. This hyporesponsiveness, which was demonstrated by specific inhibition of mixed leukocyte culture (MLC), inhibition of cytotoxic T lympholysis (CTL), specific suppression of the delayed type hypersensitivity (DTH) response, and prolongation of specific skin allograft survival, was adoptively transferable by CD8+ radiosensitive T lymphocytes. In this study, we extend those results to evaluate the effects of an immunosuppressive agent (prednisolone) and an alkylating drug (cyclophosphamide) on the induction of this specific suppressive cellular response. Our results reveal that the administration of prednisolone reduces the induction of the specific hyporesponsiveness to alloantigen, as demonstrated by maintenance of the DTH response to alloantigen and continued accelerated rejection of skin allografts. In contrast, the administration of cyclophosphamide augmented this specific suppressive response to alloantigen in the DTH assay and in prolongation of specific skin allograft survival. These results indicate that adjuvant immunomodulating chemotherapy alters the immune response to photoinactivated effector T cells.

Induction of a cell-transferable suppression of alloreactivity by photodamaged lymphocytes.

We have reported previously that splenocytes from BALB/c mice acutely rejecting CBA/j skin allografts were exposed to 8-methoxypsoralen (8-MOP) and ultraviolet A light and infused several times intravenously into naive BALB/c recipients; the recipients were hyporesponsive to CBA/j alloantigens in skin graft and delayed-type hypersensitivity assays, as well as in mixed leukocyte culture and cytotoxicity assays. We currently expand on this work by showing that donor-specific tolerance can be transferred adoptively to naive syngeneic animals via unfractionated splenocytes from mice rendered tolerant by the previous protocol. This suppressed response to alloantigen was transferred optimally with splenocytes taken from mice on the sixth day after the final treatment with PET cells. We further demonstrate that the cells that are adoptively transferring suppression are radiosensitive, Thy-1+, Lyt-2+, L3T4− T lymphocytes.