Richard L. Edelson

Cutaneous T cell lymphoma: Mycosis fungoides, Sézary syndrome, and other variants

Cutaneous T cell lymphoma (CTCL) is a clinically and immunologically defined neoplasm which encompasses epidermotropic (mycosis fungoides, Sézary syndrome) and nonepidermotropic variants. A natural evolution apparently occurs from the epidermotropic to the nonepidermotropic form. In this review, cellular properties of the neoplastic cells are correlated with specific clinical observations, and recent therapeutic advances are discussed. Advances in our understanding of the pathogenesis of CTCL, including preliminary evidence suggesting that keratinocytes may elaborate a hormonal substance capable of inducing T lymphocyte differentiation, are discussed.

In situ identification of Langerhans cells in the dermal infiltrate of cutaneous T cell lymphoma

A population of cells showing the surface phenotype of Langerhans cells (LCs) was identified in the dermal infiltrates of cutaneous T cell lymphoma (CTCL). Peroxidase-conjugated OKT6, a monoclonal antibody reactive with epidermal LCs, was used to directly label frozen tissue sections of diseased skin from twenty-three patients with CTCL, two patients with secondary cutaneous involvement by a B cell lymphoma, and three patients with lymphocytoma cutis. OKT6-reactive cells represented a significant although minor population in the dermal infiltrate of twenty-two of the twenty-three CTCL biopsies, accounting for up to 5% of the cells. Double-labeling studies revealed that the OKT6-positive cells also exhibited Ia but not T cell antigens. Since OKT6-reactive cells were not found in either the B cell lymphomas or lymphocytoma cutis, their presence in a malignant infiltrate is suggestive of a T cell neoplasm.

Clonal chromosomal abnormalities in cutaneous T-cell lymphoma.

Chromosome analysis from stimulated and unstimulated lymphocytes of blood, skin, and lymph nodes demonstrated a clonal chromosomal abnormality in eight of 46 patients with cutaneous T-cell lymphoma (CTCL). Nonclonal abnormalities were found in nine other patients. Unstimulated lymph node cultures identified the highest proportion of clonal changes. Clonal changes were found most often in patients with advanced disease, and in patients who tested positive with a monoclonal antibody previously shown to detect the T-cells involved in CTCL. Analysis of the eight abnormal clones and seven others found before or since this consecutive series showed that identifiable changes involving the known sites of T-cell receptor genes on chromosomes #7 and #14 were not usually present. An association between CTCL and chromosome rearrangements of chromosome #10 is suggested both from our cases and those found in the literature. This observation is of interest because this chromosome contains the gene for the interleukin-2 receptor.

WAVELENGTH DEPENDENCE FOR AMT CROSSLINKING OF pBR322 DNA

Abstract The wavelength dependence for 4′aminomethyl‐4,5′,8‐trimethylpsoralen crosslinking of a linearized plasmid DNA (pBR322) by narrow band UV‐A light (298–382 nm) has been determined. Maximal levels of crosslinking occurred with light in the 322–346 nm range. Crosslinks were shown to be photoreversible by shorter wavelength photons (298 and 310 nm). The correlation between the wavelength dependence for crosslink formation and the optimal wavelength for most psoralen action spectra further supports the notion that crosslinks are the major lesion responsible for the effectiveness of psoralen plus ultraviolet A therapies.

Normal numbers of phenotypic helper, suppressor, and total T cell populations in psoriasis vulgaris: Quantitation by monoclonal antibodies

Previous studies of E rosette-forming cells in the blood of patients with psoriasis vulgaris have demonstrated conflicting results. Availability of a battery of monoclonal antibodies permitted quantitation of individual T cell populations in patients with psoriasis. Peripheral blood mononuclear leukocytes from twelve patients with extensive, active psoriasis and from fifteen normal controls were studied by indirect immunofluorescence. No statistically significant differences from control values were identified (p values were all greater than or equal to 0.4). These monoclonal antibodies provide highly specific reagents, previously not available, for identifying different lymphocyte phenotypes. Analysis of the data indicates that shifts in major T lymphocyte subpopulations are not present in patients with active psoriasis.

Pathogenesis of Cutaneous T-Cell Lymphoma

Cutaneous T-cell lymphoma is a malignant disease whose behavior reflects its T-cell lineage. The biologic characteristics of the disease are understandable when viewed from a perspective of normal T-cell-skin interactions. Thus, it is of no surprise that this malignancy of helper T lymphocytes usually demonstrates a remarkable affinity for the skin at the outset and that, coincident with decreased dependence upon this unique environment, the extent and aggressiveness of disease increases. Although the inciting event responsible for the development of cutaneous T-cell lymphoma is unknown, a mechanism for local growth and distant expansion of malignant cells has been postulated in terms of IL-2-dependent and -independent growth phases. As our vision into the cellular and subcellular workings of this malignancy becomes more acute, specific therapeutic and preventive measures will emerge.

HPLC analysis of 4',5'-monoadduct formation in calf thymus DNA and synthetic polynucleotides treated with UVA and 8-methoxypsoralen.

Abstract— 8‐methoxypsoralen monoadduct formation in calf thymus DNA irradiated with subbands of ultraviolet A light has been quantitated by HPLC analysis of the enzymatic hydrolysates of the DNA. Normalization of the yield of monoadducts for the variation in source output and the absorptivity of 8‐MOP at each of the irradiating wavelengths showed that the 4′,5′‐furan monoadduct was the principal photoproduct and the efficiency of its formation was independent of irradiating wavelength. Synthetic polynucleotides irradiated with ultraviolet A light demonstrated a base composition and sequence dependence for 8‐MOP photoreactivity: (poly(dAdT.dAdT) > poly(dA.dT) > poly(dGdC.dGdC) in both the B and Z forms > pofy(dT).

THYMOPOIETIN-LIKE SUBSTANCE IN HUMAN SKIN

A heterologous antithymopoietin (anti-TP) antibody was used to determine whether a TP-like molecule is present in the epidermis, since such factors have been postulated to play a part in known T cell-epidermal cell interaction. Examination of cytocentrifuge smears of freshly separated human epidermal cells stained by indirect immunofluorescence revealed that 8-14% of these cells possessed cytoplasmic reactivity with the anti-TP antibody. Similarly, 2-5% of human epidermal cells, maintained in tissue culture for 2-8 weeks, showed cytoplasmic staining with the anti-TP antibody. Double-labeling immunofluorescence studies, with the anti-TP antibody and a monoclonal antibody specifically reactive with Langerhans cells (OKT6), demonstrated that cells possessing this TP-like substance were not Langerhans cells. In situ studies of 4-microns frozen sections of normal human skin indicated that the cell population which possesses the TP-like substance is the basal layer of keratincoytes in the epidermis.

Inhibition of Antiskin Allograft Immunity Induced by Infusions with Photoinactivated Effector T Lymphocytes (PET Cells). Is In Vivo Cell Transferrable

We previously reported producing donor-specific tolerance to alloantigens by intravenous exposure to pretreated antidonor T cells. The current study extends that work by adoptively transferring the donor-specific tolerance into naive syngeneic recipients. Eight days after BALB/c mice received histoincompatible CBA/j skin grafts, their splenocytes which included an expanded population of cells mediating rejection were treated with 100 ng/ml 8-methoxypsoralen (8-MOP) photoactivated by 1 Joule/cm2 of ultraviolet A (UVA) light prior to infusion into naive BALB/c recipients. Whereas 8-MOP itself is biologically inert, photoactivated 8-MOP crosslinks DNA by covalently binding to pyrimidine bases. Recipient BALB/c mice which had been previously demonstrated to be hyporesponsive to CBA/j alloantigens in mixed leukocyte culture (MLC), cytotoxicity (CTL) and in vivo delayed type hypersensitivity (DTH) assays were the donors of spleen cells for the adoptive transfer experiments. Fifty to one hundred million viable spleen cells from these pretreated BALB/c mice were transferred into naive syngeneic recipients which then were tested for DTH response and allograft survival to the relevant and irrelevant antigens. The radiosensitivity of this transferrable suppression was evaluated by exposing the adoptively transferred cell population to 3200 rads of C-irradiation prior to cell transfer. The phenotype of the cells transferring this suppressive response was performed by depleting specific populations of cells with monoclonal antibodies prior to cell transfer. In vivo the DTH response of the pretreated BALB/c mice was specifically suppressed to the relevant alloantigen, correlating with retention of CBA/j skin grafts for up to 42 days post engraftment without visual evidence of rejection, in comparison to control mice complete rejection of the skin graft in less than 8 days. In vitro, splenocytes from BALB/c recipients of pretreated syngeneic splenocytes containing large numbers of BALB/c anti-CBA/j T cells proliferated less in MLC and generated lower cytotoxic T cell responses to CBA/j alloantigens than did controls and suppressed the naive and sensitized BALB/c MLC and CTL responses to CBA/j alloantigen. This specific suppressive response to alloantigen was optimally transferred into syngeneic naive recipients when the adoptive transfer was performed on the sixth day after the last infusion received by the spleen cell donor mice. The adoptive transfer of this suppressive response was abrogated by the prior X-irradiation of the donor spleen cells and significantly abolished by the depletion of Thy-1+, Lyt-2+, L3T4- T lymphocytes.(ABSTRACT TRUNCATED AT 400 WORDS)

Locomotion of T cells from patients with cutaneous T-cell lymphoma (Sezary syndrome and mycosis fungoides)

Abstract Peripheral blood T cells from eight patients with cutaneous lymphoma (four each with Sezary syndrome or mycosis fungoides) and T cells from skin tumor of one patient each with Sezary syndrome or mycosis fungoides were studied for their locomotor responses to the chemoattractant, casein. Nonmalignant peripheral blood T cells from each patient with mycosis fungoides moved normally. Malignant T cells from skin tumor of patients with mycosis fungoides or Sezary syndrome did not move in the presence of casein. Peripheral blood malignant T cells (Sezary cells) from three of four patients with Sezary syndrome either moved very poorly or did not move at all. The circulating Sezary cells from the fourth patient with Sezary syndrome responded moderately to the chemoattractant, casein. Two of three patients with Sezary syndrome with poor or no locomotor response of T cells underwent therapeutic leukopheresis without any demonstrable effect on their skin infiltration. The patient whose malignant T cells demonstrated moderate locomotor response to casein had a leukemic blast crisis and at that time her skin became free of malignant cells. A repeat study of her circulating T cells at that time demonstrated almost normal locomotor response to casein. These results demonstrate that the locomotor properties of malignant T cells in patients with Sezary syndrome may have prognostic significance.