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CANDIDIASIS--IMMUNO-INHIBITION BY MANNAN CATABOLITES

念珠菌病--甘露聚糖分解代谢物的免疫抑制

基本信息

批准号：
3139456
负责人：
ROBERT D NELSON
金额：
$ 13.04万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
1988
资助国家：
美国
起止时间：
1988-07-01 至 1993-06-30
项目状态：
已结题

项目摘要

This application describes experiments to define the immuno- inhibitory property of yeast mannan which contributes to the pathogenesis of chronic candidiasis. We and others have demonstrated that a blocking factor of cell-mediated immunity in plasma from patients with chronic candidiasis is mannan polysaccharide derived from the cell wall of the pathogen. Remaining unknown are the structure of the immuno-inhibitory manan and the mechanism of inhibition. Our WORKING HYPOTHESIS is that mannan released from growing and phagocytized organisms is catabolized by local macrophages and fixed macrophages of the reticuloendothelial system. Mannan in its native form is an effective antigen for stimulation of T- lymphocyte proliferation, but mannan catabolites released by the macrophages are potently immuno-inhibitory. This property of mannan catabolites represents a significant novel clue to the mechanism of anergy associated with chronic candidiasis. Such catabolites are mannose oligosaccharides ranging in size from dimer to oligomers containing six or more sugar residues. Immuno-inhibitory activity correlates with increasing size. Inhibition of antigen-stimulated lymphoproliferation is not related to toxicity of the oligomers for lymphocytes or monocytes, but rather involves an inhibitory effect on either cytokine production or activity. Anti-mannan antibodies, although present in high titer in patient serum, are not able to neutralize the immuno- inhibitory catabolites because these mannose oligomers are not antigenic. Failure of antibody to recognize the oligomers may be due to their catabolic release from a linkage with the antigenic property (i.e., the direct O-linkage of mannose to serine/threonine) and possibly also because the free oligomers mimic the carbohydrate portions of many normal glycoproteins. Antimannan antibody may, in fact, promote the clearance of serum mannan and thereby promote its catabolism and generation of the immuno-inhibitory oligomers. This hypothesis is based upon considerable supportive preliminary data generated in our laboratory. Detailed structural and functional aspects of immuno-inhibitory mannose oligosaccharides are significant because Candida spp. Are becoming more frequent pathogens for an increasing number of patients including those receiving medical therapies which interfere with host defense, those with chronic and debilitating diseases, and persons with AIDS. We offer that clues to more effective therapy for prevention and treatment of chronic candidiasis will derive from results to be obtained as well as clues to the modulation of immune function in both normal and other infectious or pathological states.

本应用程序描述了定义免疫的实验