RESUMO
Approximately 88% of cutaneous T-cell lymphoma (CTCL) patients are affected by pruritus that responds poorly to current antipruritic therapies. Interleukin (IL)-31, a Th2 cytokine, has been found to be increased in the serum of CTCL patients and to correlate with itch severity. This study investigated the role of IL-31 and its receptors (IL-31 receptor-alpha [IL-31RA] and OSMRß) in the skin of CTCL patients with mild versus moderate/severe pruritus. Expression levels of IL-31, IL-31RA, and OSMRß in the skin were measured using immunohistochemistry and correlated to pruritus severity and disease stage. In CTCL patients with moderate/severe pruritus, IL-31 was significantly elevated in the epidermis and dermal infiltrate, while IL-31RA and OSMRß were significantly elevated only in the epidermis. Furthermore, epidermal IL-31 levels correlated to itch severity. These results show that IL-31 may play a role in CTCL pruritus by exerting indirect effects on sensory nerves through epidermal neoplastic T cells and keratinocytes to transmit itch.
Assuntos
Interleucinas/metabolismo , Linfoma Cutâneo de Células T/metabolismo , Subunidade beta de Receptor de Oncostatina M/metabolismo , Prurido/metabolismo , Receptores de Interleucina/metabolismo , Idoso , Biópsia , Feminino , Humanos , Imuno-Histoquímica , Masculino , Índice de Gravidade de DoençaRESUMO
Pruritus is one of the cardinal symptoms found in patients with leukemic cutaneous T cell lymphoma (CTCL). The nature of the pruritus experienced by CTCL patients is complex, involving different pathways and cell mediators, thus making it poorly responsive to conventional anti-itch therapies. Recent reports highlight the role of interleukin 31 (IL-31) as a novel cytokine involved in the pathogenesis of pruritus in atopic dermatitis and CTCL. Here we provide both in vivo and in vitro evidence suggesting that histone deacetylase (HDAC) inhibitors may mitigate itch through lowering of levels of IL-31-expressing T cells. Furthermore, we demonstrate that chemokine receptor type-4 (CCR4)-bearing T cells are a main source of IL-31 in CTCL, and that neutralizing the IL-31 pathway through targeting of the CCR4-expressing T cells may represent a promising therapeutic strategy for symptomatic relief in CTCL.
Assuntos
Inibidores de Histona Desacetilases/uso terapêutico , Interleucinas/imunologia , Linfoma Cutâneo de Células T/tratamento farmacológico , Prurido/tratamento farmacológico , RNA Mensageiro/metabolismo , Neoplasias Cutâneas/tratamento farmacológico , Linfócitos T/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Depsipeptídeos/farmacologia , Depsipeptídeos/uso terapêutico , Dexametasona/farmacologia , Dexametasona/uso terapêutico , Feminino , Inibidores de Histona Desacetilases/farmacologia , Humanos , Ácidos Hidroxâmicos/farmacologia , Ácidos Hidroxâmicos/uso terapêutico , Técnicas In Vitro , Linfoma Cutâneo de Células T/complicações , Linfoma Cutâneo de Células T/imunologia , Masculino , Pessoa de Meia-Idade , Prurido/etiologia , Prurido/imunologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Neoplasias Cutâneas/complicações , Neoplasias Cutâneas/imunologia , Linfócitos T/efeitos dos fármacos , Resultado do Tratamento , VorinostatRESUMO
Sézary syndrome (SS) cells express cell surface molecules also found on normal activated CD4 T cells. In an effort to find a more specific surface marker for malignant SS cells, a microarray analysis of gene expression was performed. Results showed significantly increased levels of mRNA for CD164, a sialomucin found on human CD34+ hematopoietic stem cells, and FCRL3, a molecule present on a subset of human natural T regulatory cells. Both markers were increased in CD4 T cells from SS patients compared with healthy donors (HD). Flow cytometry studies confirmed the increased expression of CD164 and FCRL3 primarily on CD4+CD26- T cells of SS patients. Importantly, a statistically significant correlation was found between an elevated percentage of CD4+CD164+ T cells and an elevated percentage of CD4+CD26- T cells in all tested SS patients but not in patients with mycosis fungoides and atopic dermatitis or HD. FCRL3 expression was significantly increased only in patients with high tumor burden. CD4+CD164+ cells displayed cerebriform morphology and their loss correlated with clinical improvement in treated patients. Our results suggest that CD164 can serve as a marker for diagnosis and for monitoring progression of cutaneous T-cell lymphoma (CTCL)/SS and that FCRL3 expression correlates with a high circulating tumor burden.