isotretinoin and Common-Variable-Immunodeficiency

The underlying nature of the defect of CVID is not understood, and the treatment at present is life-long infusion of replacement immunoglobulin. Attempts have been made to use other therapeutic agents, such as IL-2 and retinoic acid (RA), with mixed results. RA is a morphogenetic signalling molecule related to vitamin A and involved in vertebrate development. We report here our in vitro evaluation of the effects of three vitamin A analogues, 9-cis retinal, 13-cis RA and all-trans RA, on antibody production of PBMC from normal donors and patients with CVID. At 10(-5) M, 9-cis retinal strongly augmented IgM production of lymphocytes from normal individuals and to a much lesser extent, mild, non-granulomatous (group C) CVID patients, but IgG production was not affected. In the presence of anti-human IgM and IL-2, 9-cis retinal at 10(-5) M elevated IgM and IgG production by normal PBMC, but the effect on PBMC of mild CVID was minimal. The effect of 9-cis retinal was significantly reduced at 10(-7) and 10(-9) M. Only minimal effects were found using 13-cis RA and all-trans RA under these conditions. No detectable antibody production was found in severe, granulomatous (group A) CVID patients under any conditions tested. Taking all data into account, 9-cis retinal is the most potent stimulator for antibody production compared with 13-cis RA and all-trans RA as tested in this in vitro study.

Topics: Blood Donors; Cells, Cultured; Common Variable Immunodeficiency; Diterpenes; Humans; Immunoglobulins; Isotretinoin; Leukocytes, Mononuclear; Retinaldehyde; Tretinoin; Vitamin A

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.

Topics: Adolescent; Adult; Antigens, Surface; B-Lymphocytes; Base Sequence; Cell Differentiation; Common Variable Immunodeficiency; Drug Administration Schedule; Female; Gene Expression; Genes, Immunoglobulin; Humans; Immunization; Immunoglobulin G; Immunoglobulin M; Immunoglobulins; Interleukin-6; Isotretinoin; Male; Middle Aged; Molecular Sequence Data; Oligonucleotides