RESUMEN
Rituximab, a monoclonal antibody targeting CD20 on B cells, is currently used to treat many subtypes of B cell lymphomas. However, treatment is not curative and response rates are variable. Recombinant interleukin-21 (rIL-21) is a cytokine that enhances immune effector function and affects both primary and transformed B cell differentiation. We hypothesized that the combination of rIL-21 plus rituximab would be a more efficacious treatment for B cell malignancies than rituximab alone. We cultured human and cynomolgus monkey NK cells with rIL-21 and found that their activity was increased and proteins associated with antibody dependent cytotoxicity were up-regulated. Studies in cynomolgus monkeys modeled the effects of rIL-21 on rituximab activity against CD20 B cells. In these studies, rIL-21 activated innate immune effectors, increased ADCC and mobilized B cells into peripheral blood. When rIL-21 was combined with rituximab, deeper and more durable B cell depletion was observed. In another series of experiments, IL-21 was shown to have direct antiproliferative activity against a subset of human lymphoma cell lines, and combination of murine IL-21 with rituximab yielded significant survival benefits over either agent alone in xenogeneic mouse tumor models of disseminated lymphoma. Therefore, our results do suggest that the therapeutic efficacy of rituximab may be improved when used in combination with rIL-21.
Asunto(s)
Anticuerpos Monoclonales de Origen Murino/farmacología , Antineoplásicos/farmacología , Linfocitos B/citología , Linfocitos B/efectos de los fármacos , Interleucinas/farmacología , Linfoma de Células B/tratamiento farmacológico , Linfoma de Células B/inmunología , Animales , Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Citotoxicidad Celular Dependiente de Anticuerpos/efectos de los fármacos , Antineoplásicos/uso terapéutico , Linfocitos B/inmunología , Línea Celular Tumoral , Modelos Animales de Enfermedad , Sinergismo Farmacológico , Femenino , Humanos , Inmunidad Innata/efectos de los fármacos , Linfoma de Células B/patología , Macaca fascicularis , Masculino , Ratones , Rituximab , Análisis de SupervivenciaRESUMEN
Psoriasis is a common chronic skin disease with a largely unknown pathogenesis. We demonstrate here that transgenic over-expression of interleukin (IL)-22 in mice resulted in neonatal mortality and psoriasis-like skin alterations including acanthosis and hypogranularity. This cutaneous phenotype may be caused by the direct influence of IL-22 on keratinocytes, since this cytokine did not affect skin fibroblasts, endothelial cells, melanocytes, or adipocytes. The comparison of cytokines with hypothesized roles in psoriasis pathogenesis determined that neither interferon (IFN)-gamma nor IL-17, but only IL-22 and, with lower potency, IL-20 caused psoriasis-like morphological changes in a three-dimensional human epidermis model. These changes were associated with inhibited keratinocyte terminal differentiation and with STAT3 upregulation. The IL-22 effect on differentiation-regulating genes was STAT3-dependent. In contrast to IL-22 and IL-20, IFN-gamma and IL-17 strongly induced T-cell and neutrophilic granulocyte-attracting chemokines, respectively. Tumor necrosis factor-alpha potently induced diverse chemokines and additionally enhanced the expression of IL-22 receptor pathway elements and amplified some IL-22 effects. This study suggests that different cytokines are players in the psoriasis pathogenesis although only the IL-10 family members IL-22 and IL-20 directly cause the characteristic epidermal alterations.
Asunto(s)
Epidermis/efectos de los fármacos , Interferón gamma/farmacología , Interleucina-17/farmacología , Interleucinas/farmacología , Animales , Western Blotting , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Quimiocinas/genética , Quimiocinas/metabolismo , Sinergismo Farmacológico , Ensayo de Inmunoadsorción Enzimática , Epidermis/metabolismo , Epidermis/patología , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Fibroblastos/patología , Humanos , Inmunohistoquímica , Interleucinas/genética , Interleucinas/metabolismo , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Queratinocitos/patología , Ratones , Ratones Endogámicos , Ratones Transgénicos , Psoriasis/genética , Psoriasis/metabolismo , Psoriasis/patología , Interferencia de ARN , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo , Factor de Necrosis Tumoral alfa/farmacología , Interleucina-22RESUMEN
T cell-derived cytokines are important in the development of an effective immune response, but when dysregulated they can promote disease. Here we identify a four-helix bundle cytokine we have called interleukin 31 (IL-31), which is preferentially produced by T helper type 2 cells. IL-31 signals through a receptor composed of IL-31 receptor A and oncostatin M receptor. Expression of IL-31 receptor A and oncostatin M receptor mRNA was induced in activated monocytes, whereas epithelial cells expressed both mRNAs constitutively. Transgenic mice overexpressing IL-31 developed severe pruritus, alopecia and skin lesions. Furthermore, IL-31 receptor expression was increased in diseased tissues derived from an animal model of airway hypersensitivity. These data indicate that IL-31 may be involved in promoting the dermatitis and epithelial responses that characterize allergic and non-allergic diseases.
Asunto(s)
Dermatitis/inmunología , Dermatitis/patología , Interleucinas/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismo , Secuencia de Aminoácidos , Animales , Citometría de Flujo , Eliminación de Gen , Perfilación de la Expresión Génica , Humanos , Hipersensibilidad/inmunología , Hipersensibilidad/patología , Bombas de Infusión Implantables , Interleucinas/química , Interleucinas/genética , Interleucinas/farmacología , Pulmón/inmunología , Pulmón/patología , Activación de Linfocitos , Ratones , Ratones Noqueados , Ratones Transgénicos , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores de Citocinas/genética , Receptores de Interleucina/química , Receptores de Interleucina/genética , Receptores de Interleucina/metabolismo , Receptores de Oncostatina M , Transgenes/genética , Regulación hacia ArribaRESUMEN
mdr1a-deficient mice lack P-glycoprotein and spontaneously develop colitis with age. Helicobacter spp. are gram-negative organisms that have been associated with colitis in certain mouse strains, but Helicobacter spp. have been excluded as contributing to the spontaneous colitis that develops in mdr1a-/- mice. We wished to determine whether infection with either H. bilis or H. hepaticus would accelerate the development of inflammatory bowel disease (IBD) in mdr1a-/- mice. We found that H. bilis infection induced diarrhea, weight loss, and IBD in mdr1a-/- mice within 6 to 17 weeks post-inoculation and before the expected onset of spontaneous IBD. Histopathology of H. bilis-induced IBD included crypt hyperplasia, inflammatory cell infiltrates, crypt abscesses, and obliteration of normal gut architecture. Reverse transcription-polymerase chain reaction and Taqman analysis from colonic tissue showed increased transcripts for interferon-gamma and interleukin-10 from H. bilis-infected colitic mdr1a-/- mice. Additionally, mesenteric lymph nodes had increased cellularity with expansion of CD4+ and CD8+ T cells and B cells and increased proliferation to soluble H. bilis antigens with elaboration of interferon-gamma, tumor necrosis factor-alpha and interleukin-10. In contrast, H. hepaticus infection of mdr1a-/- mice did not accelerate disease but rather delayed the onset of spontaneous colitis which was milder in severity. mdr1a-/- mice infected with Helicobacter spp. may provide a useful tool to explore the pathogenesis of microbial-induced IBD in a model with a presumed epithelial cell "barrier" defect.