CANDIDIASIS--IMMUNO-INHIBITION BY MANNAN CATABOLITES

本申请描述了定义免疫调节剂的实验。 酵母甘露聚糖的抑制特性， 慢性念珠菌病的发病机制。 我们和其他人已经 证明了细胞介导的免疫的阻断因子， 来自慢性念珠菌病患者的血浆是甘露聚糖 来源于病原体细胞壁的多糖。 仍然未知的是免疫抑制剂的结构 甘露聚糖及其抑制机制。 我们的工作 假设是甘露聚糖从生长和 被吞噬的生物体被局部巨噬细胞分解代谢， 网状内皮系统的固定巨噬细胞。 中甘露聚糖 其天然形式是刺激T细胞的有效抗原， 淋巴细胞增殖，但甘露聚糖释放的 巨噬细胞是有效的免疫抑制剂。 的这种性质 甘露聚糖催化剂代表了一个重要的新线索， 与慢性念珠菌病相关的无反应机制。 等 甘露寡糖是甘露糖寡糖，其大小范围为 二聚体到含有六个或更多个糖残基的寡聚体。 免疫抑制活性与增加的尺寸相关。 抑制抗原刺激的淋巴细胞增殖无关 低聚物对淋巴细胞或单核细胞的毒性，但 而是涉及对细胞因子产生的抑制作用， 或活动。 抗甘露聚糖抗体，虽然存在于高 患者血清中的滴度，不能中和免疫- 因为这些甘露糖低聚物不 抗原性的 抗体不能识别寡聚体可能是 由于它们从与抗原结合的分解代谢释放， 特性（即，甘露糖的直接O-键合， 丝氨酸/苏氨酸），也可能是因为游离的低聚物 模拟许多正常糖蛋白的碳水化合物部分。 事实上，抗甘露聚糖抗体可以促进 血清甘露聚糖，从而促进其分解和生成 免疫抑制性寡聚体。 这个假设是基于 在我们的研究中产生了大量支持性的初步数据， 实验室 详细的结构和功能方面 免疫抑制性甘露寡糖是重要 因为念珠菌属（Candida spp.） 越来越多的病原体 越来越多的病人，包括那些接受 干扰宿主防御的药物治疗， 慢性病和使人衰弱的疾病以及艾滋病患者。 我们 为更有效的预防治疗提供了线索， 慢性念珠菌病的治疗将来自于 获得的以及调节免疫功能的线索， 正常和其它感染或病理状态。

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.