CANDIDIASIS--IMMUNO-INHIBITION BY MANNAN CATABOLITES

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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.