Complete molecular remission during biologic response modifier therapy for Sézary syndrome is associated with enhanced helper T type 1 cytokine production and natural killer cell activity.

BACKGROUND: Cutaneous T-cell lymphoma (CTCL) is a clonally derived, skin-invasive malignancy of CD4(+) T lymphocytes with the phenotype of mature helper T cells. Advancing stages of CTCL are associated with depressed cell-mediated immunity, increased production of T helper type 2 cytokines and decreased levels of T helper type 1 cytokines. OBJECTIVE: Our purpose was to evaluate the cytokine secretion pattern and cell-mediated cytotoxicity in peripheral blood mononuclear cells of patients with Sézary syndrome in relation to the presence of the malignant clone. METHODS: Serial polymerase chain reaction for the T-cell receptor-beta or T-cell receptor-gamma gene rearrangement was used to determine the presence of the malignant clone. Enzyme-linked immunosorbent assays were used to determine the levels of interleukin 4 and interferon gamma produced by the peripheral blood mononuclear cells from the patients with Sézary syndrome. RESULTS: We demonstrate 3 cases of Sézary syndrome with typically suppressed cell-mediated cytotoxicity, elevated production of interleukin 4, and depressed production of interferon gamma by their peripheral blood mononuclear cells before institution of therapy with biologic response modifier therapy. In all 3 cases after clinical and molecular remission, we observed striking immunologic changes, including an increase in levels of natural killer cell activity and interferon gamma production and decreased production of interleukin 4. CONCLUSIONS: The observation that the cytokine secretion pattern by peripheral blood mononuclear cells from 3 patients with Sézary syndrome normalized with the disappearance of the malignant clone from the peripheral blood suggests that the malignant T cells account for the aberrant cytokine production. Moreover, the aberrant cytokine production may be the cause for suppression of cell-mediated immunity seen in advancing stages of CTCL.

Photopheresis: clinical applications and mechanism of action.

Photopheresis is a leukapheresis-based therapy that utilizes 8-methoxypsoralen and ultraviolet A irradiation. Photopheresis is currently available at approximately 150 medical centers worldwide. Recent evidence suggests that this therapy used as a single agent may significantly prolong life, as well as induce a 50%-75% response rate among individuals with advanced cutaneous T cell lymphoma (CTCL). Furthermore, a 20%-25% complete response rate with photopheresis alone, or in combination with other biologic response modifiers, has been obtained at our institution among patients with Sezary syndrome. These complete responses have been characterized by the complete disappearance of morphologically atypical cells from the skin and blood. The use of sensitive molecular techniques has also confirmed the sustained disappearance of the malignant T cell clone from the blood of patients with complete responses. In addition to the treatment of CTCL, numerous reports indicate that photopheresis is a potent agent in the therapy of acute allograft rejection among cardiac, lung, and renal transplant recipients. Chronic graft versus host disease also appears to be quite responsive to photopheresis therapy. Likewise, there may also be a potential role for photopheresis in the therapy of certain autoimmune diseases that are poorly responsive to conventional therapy. The immunologic basis for the responses of patients with these conditions is likely due to the induction of anticlonotypic immunity directed against pathogenic clones of T lymphocytes. Treatment-induced apoptotic death of pathogenic T cells and activation of antigen presenting cells are postulated to have important effects in this therapeutic process.

Interleukin-12 therapy of cutaneous T-cell lymphoma induces lesion regression and cytotoxic T-cell responses.

Progression of cutaneous T-cell lymphoma (CTCL) is associated with profound defects in cell-mediated immunity and depressed production of cytokines, which support cell-mediated immunity. Because we have observed marked defects in interleukin-12 (IL-12) production in CTCL and because IL-12 is critical for antitumor cytotoxic T-cell responses, we initiated a phase I dose escalation trial with recombinant human IL-12 (rhIL-12) where patients received either 50, 100, or 300 ng/kg rhIL-12 twice weekly subcutaneously or intralesionally for up to 24 weeks. Ten patients were entered: 5 with extensive plaque, 3 with Sezary syndrome, and 2 with extensive tumors with large cell transformation. One patient with Sezary syndrome dropped out after 1 week for personal reasons. Subcutaneous dosing resulted in complete responses (CR) in 2 of 5 plaque and partial responses (PR) in 2 of 5 plaque, and 1 of 2 Sezary syndrome (overall response rate CR+PR 5 of 9, 56%). A minor response also occurred in 1 of 5 plaque patients. Intralesional dosing resulted in individual tumor regression in 2 of 2 patients. Biopsy of regressing lesions showed a significant decrease in the density of the infiltrate in all cases and complete resolution of the infiltrate among those with clinical lesion resolution. An increase in numbers of CD8-positive and/or TIA-1-positive T cells were observed on immunohistochemical analysis of skin biopsy specimens obtained from regressing skin lesions. Adverse effects of rhIL-12 on this regimen were minor and limited and included low-grade fever and headache. One patient discontinued rhIL-12 at week 6 because of depression. These results suggest that rhIL-12 may augment antitumor cytotoxic T-cell responses and may represent a potent and well-tolerated therapeutic agent for CTCL.

Use of biological response modifiers in the treatment of cutaneous T-cell lymphoma.

Cutaneous T-cell lymphoma (CTCL) is typically a skin-infiltrating, clonal proliferative disorder of CD4+ T cells that exhibit a T-helper type 2 cytokine phenotype. Therapeutic decisions are based on the extent of disease and the observations that host-antitumor responses occur and that these responses may be blunted by the immunosuppressive cytokines produced by the malignant T cells. Biologic response modifiers, which may enhance cell-mediated immunity and antitumor responses, are active agents in the treatment of CTCL. The rationale and use of biologic response modifiers to treat CTCL are reviewed in this article.

Apoptosis induction of ultraviolet light A and photochemotherapy in cutaneous T-cell Lymphoma: relevance to mechanism of therapeutic action.

The anti-tumor action of many chemotherapeutic agents has recently been attributed to the induction of apoptosis in the malignant cell population. In this study, we investigated the ability of extracorporeal photopheresis (ExP) and in vitro PUVA (8-methoxy-psoralen + ultraviolet A) therapy to induce apoptosis in peripheral blood mononuclear cells from Sezary syndrome patients and normal controls. Flow cytometric analysis of ExP- or PUVA-treated peripheral blood lymphocytes demonstrated two distinct cell populations within 24 h of treatment. One population was similar to untreated controls with the other exhibiting characteristics of apoptotic cell death, i.e., a loss of cell volume and an accompanying increase in cell density. This latter population was comprised of cells with DNA strand breaks as determined by the Tdt-mediated deoxyuridine triphosphate-biotin nick end labeling assay. Apoptosis was also confirmed morphologically by fluorescent and electron microscopy as well as by demonstration of characteristic DNA strand breaks (laddering) using gel electrophoresis. Apoptosis was not observed with 8-methoxypsoralen (< or = 300 ng per ml) alone; however, ultraviolet A alone at doses > or = 2 J per cm2 induced apoptosis in lymphocytes. Peripheral blood T-cell subpopulations of Sezary syndrome patients, including the malignant clone, were equally susceptible to apoptosis subsequent to either photopheresis or PUVA treatment. In contrast, monocytes (CD14+/CD45+) appear to be resistant to apoptosis induction by ExP or PUVA treatment. Moreover, ExP-treated and untreated monocytes phagocytized apoptotic, but not untreated, peripheral blood mononuclear cells. ExP and PUVA have been shown to be efficacious and well-tolerated therapies in the treatment of dermatologic diseases and transplant rejection. These data suggest that induction of apoptosis may be an important event for therapeutic efficacy.

Kinetic analysis of apoptosis induction in human cell lines by UVA and 8-MOP.

Whereas previous studies have indicated that DNA damage as a result of 8-methoxypsoralen (8-MOP) and UVA treatment leads to cell death, this study establishes the minimum concentrations of 8-MOP and UVA necessary to induce apoptosis in human T-lymphocytic and monocytic cell lines. In order to asses apoptosis, we used fluorescent microscopy to examine changes in light scattering as well as internucleosomal DNA fragmentation. Generation of a dose response curve showed that the minimum combination of UVA and 8-MOP that was necessary to induce greater than background levels of apoptosis within 24 h of treatment was 0.5 J/cm2 UVA and 12.5 ng/mL of 8-MOP. A striking observation was that UVA alone at doses > or = 1.0 J/cm2, but not 8-MOP alone (0-300 ng/mL), induced significant apoptosis in the Sup-T1 cells induced by UVA alone was not as great as that of 8-MOP and UVA in combination, a highly significant correlation between the product of the concentration of 8-MOP (ng/mL) times the dose of UVA (J/cm2) and the percentage of apoptotic cells was observed. This correlation provides an important tool for studying the relationship of UVA-induced DNA damage to apoptosis induction. moreover, it will provide a means by which early events in the apoptotic pathway can be dissected.

[Health promotion. Health promoting behavior for women's health: an analysis on meanings of Sanhujori, Korea, postpartum care].

This ethnographic exploratory study sought to define the meaning of Sanhujori from the perspective of the women who experienced it. Participant observation and interviews indicated that the women perceived the postpartum to be a new state of being, in which they underwent profound physiological, psychological, and sociological changes. Sanhujori was regarded as a phenomenon including belief system and practice system of care that would assure the successful recovery of the woman, her long-term well-being, and the health of her child. Sanhujori as a Belief System includes know-how, period, rationale, condition and consequences built upon six principles. They included: invigorating the body by augmentation of heat and avoidance of cold; resting without working; eating well; protecting the body from harmful strains; keeping cleanness; and handling with the whole heart. Sanhujori as a Practice System is a dynamic process performing according to Belief System. A failure to "Doing a Sanhujori well" was believed to put the mother at risk for a variety of ills (Sanhubyung). Influencing factors on the process included personal and environmental factors. This finding raises a basic question about the relation of professional care during the postpartum to the women's received cultural beliefs about that care.