MECHANISMS OF CYCLOSPORINE-A INHIBITION OF ANTIGEN-PRESENTING ACTIVITY IN UNINVOLVED AND LESIONAL PSORIATIC EPIDERMIS
MECHANISMS OF CYCLOSPORINE-A INHIBITION OF ANTIGEN-PRESENTING ACTIVITY IN UNINVOLVED AND LESIONAL PSORIATIC EPIDERMIS
复制标题
DOI：
10.1111/1523-1747.ep12876222
复制
发表时间：
1990-05-01
影响因子：
6.5
通讯作者：
VOORHEES, JJ
中科院分区：
文献类型：
--
作者：
COOPER, KD;BAADSGAARD, O;VOORHEES, JJ
为了阐明环孢素A对人类皮肤抗原提呈细胞亚群及其功能的影响，我们对接受环孢菌素A治疗的银屑病患者进行了研究，并在治疗前和治疗早期对银屑病患者表皮异常的免疫学参数进行了评估。我们对具有潜在抗原提呈细胞(APC)活性的皮肤活检来源的表皮细胞的功能和数量进行了定量。治疗开始后7d，正常皮肤的表皮细胞激活同种异体T细胞的抗原提呈能力被严重抑制(降低81%)(p<；0.05)。因此，环孢素A治疗抑制了未受累皮肤中朗格汉斯细胞介导的T细胞激活。相比之下，在皮损皮肤中，在这个早期时间点，表皮同种异体抗原呈递活性仅被部分抑制(55。+-。7%)(p<；0.01，n=8)。同种异体抗原提呈细胞活性降低的百分比与皮损的临床活动性降低相关，r=0.84。在三名同样在第14天接受检查的患者中，我们发现了额外的42.+-。皮损中同种异体抗原提呈活性的降低与CD1+朗格汉斯细胞数量的减少或表皮细胞释放可检测到的数量的环孢素A或其他消除T细胞同种异体反应的可溶性因子无关。银屑病皮损内抗原提呈能力抑制的时间进程和程度与非朗格汉斯细胞DR+白细胞显著减少(P<；0.01)相关(从3.0±-。1.2%至1.0。+-。第7天0.6%)(r=0.71)。环孢素A治疗与皮损皮肤中HLe1-DR+角质形成细胞的迅速和完全消失(7d时减少94%)有关，尽管此时皮肤仍与银屑病密切相关，抗原提呈细胞活性仅降低60%。综上所述，环孢菌素A至少通过两种机制干扰人表皮T细胞的激活：1)在非受累皮肤中，快速抑制朗格汉斯细胞介导的T细胞的激活；2)在皮损皮肤中，延迟抑制抗原提呈活性，这似乎与非朗格汉斯细胞DR+白细胞减少的时间进程和水平有关。后者的抗原提呈活性似乎对环孢素A耐药。在银屑病皮损中，环孢素A治疗期间皮损角质形成细胞DR表达的早期和完全丧失可能是由于对角质形成细胞DR表达至关重要的皮损T细胞淋巴因子产生减少所致。与此同时，T细胞淋巴因子对浸润性白细胞的募集和保留的减少可能导致皮损表皮中非朗格汉斯抗原提呈的白细胞的耗尽。
To elucidate how cyclosporine A affects antigen-presenting cell subsets and their function in human skin, we studied patients with psoriasis undergoing a therapeutic trial of cyclosporine A. Immunologic parameters abnormal in psoriatic epidermis were evaluated before and early in the course of therapy. We quantitated function and numbers of skin biopsy-derived epidermal cells with potential antigen-presenting cell (APC) activity. The antigen-presenting capacity of epidermal cells from normal-appearing skin to activate allogeneic T cells was profoundly inhibited (81% decrease) 7 d after the onset of therapy (p < 0.05). Thus, cyclosporine A therapy inhibited T-cell activation mediated by Langerhans cells in uninvolved skin. By contrast, in lesional skin epidermal allo-antigen presenting activity was only partially inhibited at this early time point (55 .+-. 7% decrease) (p < 0.01, n = 8). The percentage decrease in allo-antigen-presenting cell activity correlated with reduced clinical activity of the lesions, r = 0.84. In three patients also examined at 14 d, we found an additional 42 .+-. 5% decrease between day 7 and day 14. Decreased allo-antigen-presenting activity in lesional skin was not associated with a decrease in the number of CD1+ Langerhans cells or epidermal cell release of detectable amounts of cyclosporine A or other soluble factors that abrogate T-cell alloreactivity. The time course and degree of inhibition of antigen-presenting capacity within involved psoriatic skin correlated between with a significant (p < 0.01) reduction in non-Langerhans cell DR+ leukocytes (from 3.0 .+-. 1.2% to 1.0 .+-. 0.6% at day 7) (r = 0.71). Cyclosporine A therapy was associated with a rapid and complete loss of HLe1-DR+ keratinocytes (94% decrease at 7 d) in lesional skin despite the skin still being quite involved with psoriasis at this point and antigen-presenting cell activity being only 60% reduced. In conclusion, cyclosporine A interferes with T-cell activation by human epidermis through at least two mechanisms: 1) in uninvolved skin, rapid inhibition of Langerhans cell-mediated activation of T cells, and 2) in lesional skin, delayed inhibition of antigen-presenting activity which appears to correlate with the time course and level of reductions in non-Langerhans cell DR+ leukocytes. The antigen-presenting activity of the latter cells appears to be cyclosporine A resistant. In psoriatic lesions, early and complete loss of DR expression on lesional keratinocytes during cyclosporine A therapy is likely due to decreased lesional T-cell lymphokine production critical for keratinocyte DR expression. Concomitantly, decreased recruitment and retention of infiltrating leukocytes by T-cell lymphokines may result in the depletion of non-Langerhans antigen-presenting leukocytes from lesional epidermis.