Vallat V P, Gilleaudeau P, Battat L, Wolfe J, Nabeya R, Heftler N, Hodak E, Gottlieb A B, Krueger J G
Laboratory for Investigative Dermatology, Rockefeller University, New York, 10021.
J Exp Med. 1994 Jul 1;180(1):283-96. doi: 10.1084/jem.180.1.283.
Psoriasis is characterized by alterations in both the epidermis and dermis of the skin. Epidermal keratinocytes display marked proliferative activation and differentiate along an "alternate" or "regenerative" pathway, while the dermis becomes infiltrated with leukocytes, particularly interleukin 2 (IL-2) receptor-bearing "activated" T cells. Psoralens, administered by the oral route, have therapeutic effects in psoriasis when photochemically activated by ultraviolet A light (PUVA therapy). Recently psoralen bath therapy has been introduced to more effectively deliver this agent to the diseased skin. We have correlated the efficacy of PUVA bath therapy with its effects on specific molecular and cellular parameters of disease, in 10 consecutive patients with recalcitrant psoriasis. Rapid clearing of lesions occurred in 8 out of 10 patients. Biopsies were taken from lesional and nonlesional skin before and after a single round of therapy, and observation was continued in our Clinical Research Center at The Rockefeller University. Enumeration of cycling keratinocytes with the Ki-67 monoclonal antibody showed that PUVA reduced cell proliferation by 73%. The pathological increase in insulin-like growth factor 1 (IGF-1) receptors was reversed, whereas epidermal growth factor (EGF) receptors, which are also increased in psoriasis, remained unchanged. Keratinocyte proteins that are expressed in abnormal sites of the epidermis during psoriasis, i.e., keratin 16, filaggrin, and involucrin, were, after PUVA treatment, localized to their normal sites. Epidermal and dermal T-lymphocytes (CD3+), as well as CD4+, CD8+, and IL-2 receptor+ subsets, were strongly suppressed by PUVA, with virtual elimination of IL-2 receptor+ T cells in some patients. Consistent with diminished lymphocyte activation, HLA-DR expression by epidermal keratinocytes was markedly reduced in treated skin. In comparison to cyclosporine treatment of psoriasis, PUVA therapy leads to more complete reversal of pathological epidermal and lymphocytic activation, changes which we propose to be the cellular basis for a more sustained remission of disease after PUVA treatment.
银屑病的特征是皮肤的表皮和真皮均发生改变。表皮角质形成细胞表现出明显的增殖活化，并沿“替代”或“再生”途径分化，而真皮则被白细胞浸润，尤其是携带白细胞介素2（IL-2）受体的“活化”T细胞。口服补骨脂素在通过紫外线A光进行光化学激活时（PUVA疗法）对银屑病有治疗作用。最近，补骨脂素浴疗法已被引入，以便更有效地将该药物输送到患病皮肤。我们在10例连续性顽固性银屑病患者中，将PUVA浴疗法的疗效与其对疾病特定分子和细胞参数的影响进行了关联研究。10例患者中有8例皮损迅速消退。在一轮治疗前后，从皮损和非皮损皮肤处取活检组织，并在洛克菲勒大学临床研究中心继续观察。用Ki-67单克隆抗体对循环角质形成细胞进行计数显示，PUVA使细胞增殖减少了73%。胰岛素样生长因子1（IGF-1）受体的病理性增加得到逆转，而在银屑病中也增加的表皮生长因子（EGF）受体则保持不变。在银屑病期间在表皮异常部位表达的角质形成细胞蛋白，即角蛋白16、丝聚合蛋白和内披蛋白，在PUVA治疗后定位于其正常部位。PUVA强烈抑制表皮和真皮T淋巴细胞（CD3+）以及CD4+、CD8+和IL-2受体+亚群，在一些患者中几乎消除了IL-2受体+T细胞。与淋巴细胞活化减弱一致，治疗皮肤中表皮角质形成细胞的HLA-DR表达明显降低。与环孢素治疗银屑病相比，PUVA疗法能更完全地逆转病理性表皮和淋巴细胞活化，我们认为这些变化是PUVA治疗后疾病更持久缓解的细胞基础。
