CANDIDIASIS--IMMUNO-INHIBITION BY MANNAN CATABOLITES

本申请描述了定义免疫- 酵母甘露聚糖酶的抑制特性 慢性念珠菌病的发病机制。我们和其他人有 证明了一种细胞免疫的阻断因子 慢性念珠菌病患者血浆中的甘露聚糖 从病原体的细胞壁中提取的多糖。 尚不清楚的是免疫抑制的结构 甘露聚糖硫酸酯及其抑制机理。我们的工作 假说是甘露聚糖从生长和释放 吞噬的生物体被当地的巨噬细胞分解代谢 固定网状内皮系统的巨噬细胞。曼南在 其天然形式是刺激T细胞的有效抗原。 淋巴细胞增殖，但释放的甘露聚糖分解代谢 巨噬细胞具有很强的免疫抑制作用。的这一属性 甘露聚糖分解代谢代表了一条重要的小说线索 慢性念珠菌病相关的无能机制。是这样的 分解代谢物是大小不等的甘露低聚糖 二聚体到含有六个或更多糖残基的低聚物。 免疫抑制活性与大小的增加相关。 抑制抗原刺激的淋巴增殖与此无关 低聚物对淋巴细胞或单核细胞的毒性，但 而是涉及对任何一种细胞因子产生的抑制作用 或活动。抗甘露聚糖抗体，尽管存在于高水平 患者血清中的滴度，不能中和免疫- 抑制分解代谢，因为这些甘露糖低聚物不是 抗原性。抗体识别寡聚体的失败可能是 由于它们从与抗原性的链接中分解代谢释放 性质(即甘露糖与 丝氨酸/苏氨酸)，可能还因为游离低聚物 模仿许多正常糖蛋白的碳水化合物部分。 事实上，抗甘露聚糖抗体可能会促进 血清甘露聚糖，从而促进其分解代谢和生成 免疫抑制寡聚体。这一假设是基于 大量支持性的初步数据产生于我们的 实验室。详细的结构和功能方面 免疫抑制甘露糖低聚糖意义重大 因为假丝酵母菌。正变得越来越常见的病原体 越来越多的患者，包括那些接受 干扰宿主防御的药物治疗，那些 慢性和使人衰弱的疾病和艾滋病患者。我们 为更有效的预防和治疗提供线索 慢性念珠菌病的治疗将源于未来的结果 以及免疫功能调节的线索 正常状态和其他感染或病理状态。

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.