Saxon A, Keld B, Braun J, Dotson A, Sidell N
Hart and Louise Lyon Laboratory, Department of Medicine, University of California, Los Angeles School of Medicine 90024-1680.
Immunology. 1993 Nov;80(3):477-87.
We have previously shown that retinoids can induce differentiation of B cells in vitro as well as in vivo in patients with common variable immunodeficiency (CVI). While changes were observed over 1 week when retinoic acid (RA) was added to CVI hybridoma cells in vitro, maturation of the patients' B-cell compartment in vivo occurred only after 4 months of drug administration. We have now performed a 64-week open trial of oral 13-cis RA in five patients to see if prolonged treatment would result in continued improvement in their humoral immune compartment. In this trial, drug was given for 32 weeks followed by a 32-week wash-out period. During the treatment, the patients showed changes in a variety of parameters indicating an alteration towards normal of their humoral immune systems. This change included a fall in the elevated circulating interleukin-6 (IL-6) levels, a more normal display of B-cell surface markers (L-selectin and CD20), a decrease in B-cell size, and improved in vitro and in vivo B-cell function. In order to determine if VH gene use was affected by the retinoid treatment, VH gene expression in the CVI patients was characterized. Results showed an unusual predominance of non-mutated VH gene sequences, representative of cells that are recent bone marrow emigrants. While no common pattern of change occurred in VH gene segment use in the patients while on retinoid therapy, large-scale (> 10-fold) changes in the expression of these genes were observed in each individual over time. Taken together, these results provide multiple lines of evidence that 13-cis RA promotes maturation of B cells in patients with CVI. However, the effect appears to be partial, such that stimuli in addition to 13-cis RA will be necessary to provide for further B-cell differentiation in order to achieve normalization of humoral immunity.
我们之前已经表明，维甲酸类药物在体外以及在常见变异型免疫缺陷（CVI）患者体内均可诱导B细胞分化。当在体外将视黄酸（RA）添加到CVI杂交瘤细胞中时，1周内可观察到变化，而在体内，患者B细胞区室的成熟仅在给药4个月后才出现。我们现在对5例患者进行了一项为期64周的口服13 - 顺式RA开放试验，以观察长期治疗是否会使他们的体液免疫区室持续改善。在该试验中，给药32周，随后是32周的洗脱期。治疗期间，患者在各种参数上出现变化，表明其体液免疫系统趋向正常。这种变化包括循环白细胞介素 - 6（IL - 6）水平升高的情况有所下降，B细胞表面标志物（L - 选择素和CD20）的表达更趋正常，B细胞大小减小，以及体外和体内B细胞功能得到改善。为了确定VH基因的使用是否受维甲酸类药物治疗的影响，对CVI患者的VH基因表达进行了特征分析。结果显示未突变的VH基因序列异常占优势，这些序列代表近期从骨髓迁出的细胞。虽然在维甲酸类药物治疗期间患者的VH基因片段使用没有出现共同的变化模式，但随着时间推移，在每个个体中均观察到这些基因表达的大规模（> 10倍）变化。综上所述，这些结果提供了多条证据表明13 - 顺式RA可促进CVI患者B细胞的成熟。然而，这种作用似乎是部分性的，因此除了13 - 顺式RA之外，还需要其他刺激来促进B细胞进一步分化，以实现体液免疫的正常化。
