Activation of natural killer T cells by alpha-galactosylceramide treatment prevents the onset and recurrence of autoimmune Type 1 diabetes.

Type 1 diabetes (T1D) in non-obese diabetic (NOD) mice may be favored by immune dysregulation leading to the hyporesponsiveness of regulatory T cells and activation of effector T-helper type 1 (Th1) cells. The immunoregulatory activity of natural killer T (NKT) cells is well documented, and both interleukin (IL)-4 and IL-10 secreted by NKT cells have important roles in mediating this activity. NKT cells are less frequent and display deficient IL-4 responses in both NOD mice and individuals at risk for T1D (ref. 8), and this deficiency may lead to T1D (refs. 1,6-9). Thus, given that NKT cells respond to the alpha-galactosylceramide (alpha-GalCer) glycolipid in a CD1d-restricted manner by secretion of Th2 cytokines, we reasoned that activation of NKT cells by alpha-GalCer might prevent the onset and/or recurrence of T1D. Here we show that alpha-GalCer treatment, even when initiated after the onset of insulitis, protects female NOD mice from T1D and prolongs the survival of pancreatic islets transplanted into newly diabetic NOD mice. In addition, when administered after the onset of insulitis, alpha-GalCer and IL-7 displayed synergistic effects, possibly via the ability of IL-7 to render NKT cells fully responsive to alpha-GalCer. Protection from T1D by alpha-GalCer was associated with the suppression of both T- and B-cell autoimmunity to islet beta cells and with a polarized Th2-like response in spleen and pancreas of these mice. These findings raise the possibility that alpha-GalCer treatment might be used therapeutically to prevent the onset and recurrence of human T1D.

Effect of immunosuppression on the pathogenesis of respiratory zygomycosis in rabbits intranasally infected with Absidia corymbifera.

The study was envisaged for elucidating the effect of immunosuppression on the pathology and pathogenesis of experimental respiratory absidiomycosis in rabbits. Seventy rabbits used in the experiment were divided into different groups viz. non-immunosuppressed, immunosuppressed with cyclophosphamide and immunosuppressed with methylprednisolone respectively, and a control group. The experiment was continued for 50 days during which all the infected animals exhibited clinical signs of respiratory distress but no mortality. The infected rabbits showed gross lesions mainly in the form of pneumonic consolidations in the lungs in antero-ventral lobes initially followed by spread to the other lobes. Similarly, microscopic lesions were restricted to lungs and consisted of early pyogranulomas dominated by fungal invasion and spread, followed by chronic granulomatous reaction and a recovery during the later stages. Fungus was demonstrated and re-isolated only from lung lesions up to 15 days postinfection (DPI) in non-immuno-suppressed group and up to 30 DPI in both the immunosuppressed groups suggesting no systemic dissemination. The findings of the present study indicated that immunosuppression increased the extent, duration and severity of the pathological lesions associated with absidiomycosis in the lungs. Moreover, an assessment based on gross and histopathological lesions revealed cyclophosphamide to be a more potent immunosuppressant than methylprednisolone.

Effect of immunosuppression on the clinicopathological changes in experimental zygomycosis in rabbits.

A study was undertaken to investigate the effect of immunosuppression by cyclophosphamide or methylprednisolone on the clinicopathological alterations in respiratory absidiosis in rabbits. Infected rabbits showed respiratory distress that was more severe in immunosuppressed groups. Leukocytosis due to neutrophilia was observed in the non-immunosuppressed group in the initial stages, whereas leukopenia was observed in both the immunosuppressed groups initially, owing to polymorphopenia in the cyclophosphamide-treated group and to lymphopenia in the methylprednisolone-treated group, followed by leukocytosis in both groups. Total serum proteins increased significantly in the non-immunosuppressed group but were significantly decreased in the immunosuppressed groups. Serum creatinine increased significantly in all the infected groups from 20 days post inoculation (DPI) onwards. Blood urea nitrogen increased significantly in the initial stages only in the methylprednisolone-treated group. AST and ALT also showed significant increases in the infected animals. Total serum immunoglobulins and circulating immune complexes increased gradually in all three infected groups, except for an initial significant drop in the immunosuppressed rabbits. Re-isolation of fungus was only achieved from the lungs of infected rabbits up to 15 DPI in the non-immunosuppressed group and 30 DPI in the immunosuppressed groups. Pathological lesions in all the infected groups were found mainly in the lungs and consisted of pyogranulomas. The lesions were most severe in the cyclophosphamide-treated group and least severe in the non-immunosuppressed group.

Experimental zygomycosis in rabbits: clinicopathological studies.

Zygomycosis was produced experimentally in 20 New Zealand white rabbits (Oryctolagus cuniculus) by intra-nasal administration of spores of Absidia corymbifera. Infected animals showed dullness, depression, coughing and mucopurulent nasal discharge, but no mortality. Haematology revealed no significant change in Hb and PCV, but leukocytosis due to neutrophilia in the initial stages of the experiment. There was a significant increase in serum total proteins, creatinine, AST, ALT, total Igs and CICs. A. corymbifera specific IgM and IgG antibodies were detected in the sera of the infected animals. Gross lesions consisted of pneumonic consolidations of the anteroventral lobes of the lungs. Microscopically, histology showed formation of pyogranulommas in the lungs. Fungal elements typical of A. corymbifera were demonstrated in the tissues upto 15 days after infection by special stains and confirmed by indirect immunoperoxidase. Re-isolation of the fungus from lungs was also achieved consistently upto 15 days only. It was concluded that intra-nasal instillation of A. corymbifera in rabbits produced significant clinico-pathological alterations with the lesions confined mainly to the lungs. In the present study, neither systemic dissemination of the disease occurred nor were kidneys site of predilection as reported earlier.