tretinoin and Immunologic-Deficiency-Syndromes

In the myelodysplastic syndromes (MDS) clonogenic marrow cell culture studies have demonstrated intrinsic hemopoietic stem cell and progenitor cell abnormalities consistent with these disorders representing clonal hemopathies. Abnormal responsiveness of these cells to stimulatory and inhibitory growth factors indicate the contribution of regulatory abnormalities in these patients. These in vitro growth abnormalities have prognostic import and the defects progress as subsets of these patients evolve into a blastic transformation stage. Maturation-inducing agents such as retinoic acid and vitamin D alter clonal growth patterns and enhance myeloid differentiation in the MDS, and correlations between in vitro and in vivo responsiveness of hemopoietic cells to retinoic acid have been demonstrated. Studies will be reviewed indicating the role of these biologic parameters for understanding pathogenetic mechanisms underlying the MDS.

Topics: Animals; Cell Differentiation; Cell Division; Cells, Cultured; Chromosome Aberrations; Colony-Stimulating Factors; Hematopoietic Stem Cells; Humans; Immunologic Deficiency Syndromes; Lymphocyte Depletion; Lymphocytes; Mice; Myelodysplastic Syndromes; Receptors, Cell Surface; Receptors, Colony-Stimulating Factor; Tretinoin; Vitamin D

More than 50 patients with common variable immunodeficiency have been classified into 5 groups representing different blocks in B cell function. To do this, B cells were assessed in vitro by secretion of IgM or IgG in response to anti-IgM and IL-2 or to EBV alone. Some clinical features and the patients' sex ratio correlated with this B cell classification. In vitro attempts were made to identify and overcome these blocks using physiological ligands (e.g. cytokines), and agents that induce transcription (e.g. retinoic acid). The patient group with the most severely affected B cells also contained some patients whose T cells showed depressed DNA synthesis in response to mitogens. In vitro data indicate that the abnormality may be in the T cell itself rather than in monocytes failing to provide essential cytokines (e.g. IL-6). In 3 patients, splenic B cells were able to secrete IgM more effectively than circulating B cells, but still they produced no IgG.

Topics: B-Lymphocytes; Cell Division; Female; Humans; Immunoglobulin G; Immunoglobulin M; Immunoglobulins; Immunologic Deficiency Syndromes; In Vitro Techniques; Interleukin-2; Interleukin-6; Lymphocyte Activation; Male; Phytohemagglutinins; T-Lymphocytes; Transcription, Genetic; Tretinoin

Nude mice are deficient in thymus gland development and hence lacking functional, mature T-lymphocytes. Weanling nude mice were given various deficient and high retinyl palmitate (RP) or 13-cis retinoic acid (CRA) diets. The high RP (vitamin A) diets stimulated phagocytosis in the absence of mature T-helper cells. However, T-cell dependent mitogens did not cause significant mitogenesis in any group, while LPS, a B-cell mitogen, did. RP had no effect on mitogenesis. NK cell activity was increased only at a very high level of RP, as has been reported with conventional mice. Macrophage production of cytotoxic factors was unaffected by high levels of RP or CRA. Direct cytotoxicity in vitro of tumor cells was increased only at very high RP levels. Thus, mature T cells may be needed for RP to produce normal activation of macrophage, except at very high RP levels.

Topics: Animals; B-Lymphocytes; Cytotoxicity, Immunologic; Diterpenes; Female; Immunologic Deficiency Syndromes; Killer Cells, Natural; Macrophages; Melanoma; Mice; Mice, Nude; Mitogens; Phagocytosis; Retinyl Esters; T-Lymphocytes; Tretinoin; Vitamin A

Human-human B cell hybridomas constructed from B lymphocytes of common variable immunodeficiency (CVI) patients and the nonsecreting cell line WIL2/729 HF consistently secrete low levels of Ig and appear to retain a defect characteristic of the CVI patient's B cells. We assessed the differentiative capacity of retinoic acid (RA) on these hybridomas, as well as on hybridomas constructed from normal B cells and from patients with selective IgA deficiency. RA at concentrations varying between 10(-5) and 10(-9) M augmented IgM secretion 4-20-fold from four of four CVI hybridomas tested, but did not affect Ig secretion from normal or IgA-deficiency hybridomas. In support of this elevated Ig secretion, RA enhanced the de novo synthesis of biosynthetically labeled light (kappa) and heavy (mu) Ig (up to 4- and 15-fold, respectively) in the CVI hybridoma line JK32.1. The increase in IgM synthesis/secretion could not be accounted for by RA-induced alteration in the cell cycle. In inducing this increase in IgM production, RA was found to affect two aspects of Ig gene expression: (a) the steady-state levels of heavy and light chain mRNAs were enhanced, and (b) the processing of mu heavy chain transcripts to the secreted mRNA form became favored over the membrane mRNA form. We also show that expression of Leu-17 (CD38), a surface marker that is re-expressed in the late pre-plasma stage of B cell development, was increased by RA from less than 20% to greater than 90% of the total cell population, with a concomitant 4-10-fold augmentation in the mean fluorescence intensity. Changes in both Leu-17 expression and de novo Ig synthesis were prominent by 24 h, but could be observed as early as 8 h after induction. Taken together, our study demonstrates that RA affects a marked alteration in the differentiated state of the CVI hybridoma clones. This finding suggests that retinoids can enhance the functional capabilities of B cells with defects in maturation and support further studies to evaluate their clinical potential in CVI.

Topics: B-Lymphocytes; Cell Cycle; Cell Differentiation; Histocytochemistry; Humans; Hybridomas; IgA Deficiency; Immunoenzyme Techniques; Immunoglobulin M; Immunoglobulins; Immunologic Deficiency Syndromes; Phenotype; RNA, Messenger; Tretinoin

Topics: Adult; Foot; Foot Dermatoses; Humans; Immunologic Deficiency Syndromes; Isotretinoin; Male; Tretinoin; Warts

Topics: Child, Preschool; Humans; Immunologic Deficiency Syndromes; Male; Molluscum Contagiosum; Tretinoin

Darier's disease (Keratosis follicularis) a dominantly inherited keratinizing disorder of the skin, is associated with the development of severe, progressive viral and bacterial skin infections. We investigated the possibility that an inadequacy of the immune system might be responsible for this tendency. Seven of our 8 patients with Darier's disease showed complete anergy to common skin test antigens and their peripheral blood lymphocytes failed to produce the lymphokine, leukocyte inhibitory factor (LIF) in vitro when stimulated with the same antigens. One Darier's patient and 6 controls showed positivity to at least one skin test antigen and produced lymphokine in vitro to the appropriate antigen. All patients had normal leukocyte and differential counts and normal numbers of circulating T and B cells. All 8 patients with Darier's disease demonstrated no proliferative response to optimal doses of the T cell mitogen Con A while showing normal responses to the T cell stimulant PHA and the T cell dependent B cell stimulant PWM. This previously unreported finding suggests a subtle abnormality of T cells in Darier's and might be a marker for these patients. Serum from 2 patients with Darier's disease did not suppress the in vitro immunologic activity of lymphocytes from normals. Finally, 13-Cis-retinoic acid in dosages adequate to clear their skin disease did not alter the in vivo or in vitro immunologic functions in 3 Darier's patients, suggesting that the immune dysfunction is not a secondary phenomenon.

Topics: Adult; Aged; Concanavalin A; Darier Disease; Female; Humans; Immunity, Cellular; Immunologic Deficiency Syndromes; In Vitro Techniques; Isotretinoin; Leukocyte Migration-Inhibitory Factors; Lymphocyte Activation; Lymphocytes; Male; Middle Aged; Skin Tests; Tretinoin