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U Ladiwala

Publications and source records attributed to U Ladiwala.

8 recordsLinked to original sources
PubMed1998

Mechanism of gammadelta T cell-induced human oligodendrocyte cytotoxicity: relevance to multiple sclerosis.

Gammadelta T cells may contribute to the pathogenesis of Multiple Sclerosis (MS) via cytotoxicity directed at the myelin-oligodendrocyte unit. We have previously demonstrated that peripheral blood-derived gammadelta T cells lyse fresh human oligodendrocytes in vitro. The present work extends these observations to gammadelta T cells derived from both peripheral blood (PBL) and cerebrospinal fluid (CSF) of MS and non-MS neurological disease controls and addresses the mechanism of cellular cytotoxicity. We found that MS patients contained increased proportions of Vdelta1+ gammadelta T cells in both CSF and PBL samples compared to other neurological disease (OND) controls. Although gammadelta T cells from all patients were cytotoxic towards Daudi, RPMI 8226, U937, Jurkat, oligodendroglioma and fresh human oligodendrocyte targets, OND-derived, Vdelta2+ rich, populations derived from the CSF exhibited greater cytotoxicity towards cell lines (Daudi, RPMI 8226) known to express high levels of heat shock proteins (hsp). To clarify the mechanism(s) of cytotoxicity used by gammadelta T cells, we first showed that cell-target contact was necessary by the use of physical barriers (transwells), which reduced target cell lysis by at least 75%. The use of Ca2+-free media reduced lysis by up to 50%, but fully blocking gammadelta T cell Perforin release and function by either Ca2+ chelation (Mg2EGTA) or the H+-ATPase inhibitor Concanamycin-A (CMA), completely abrogated the lysis of Fas-/hsp60high expressing targets (Daudi, U937). However, additional treatment with Brefeldin A was required for the complete inhibition of gammadelta T cell mediated killing of Fas+ expressing Jurkat targets and fresh human brain-derived oligodendrocytes. Inhibition of granzyme activity by an isocoumarin compound reduced cytolysis only slightly. The use of either Brefeldin A or an anti-Fas antibody alone did not significantly affect lysis. These findings suggest that in MS, gammadelta T cells may utilize either the Fas-mediated or Perforin-based cell cytotoxicity pathways in exerting oligodendrocyte damage, though the Perforin pathway is predominant.

Brain↗
PubMed1998

p75 neurotrophin receptor expression on adult human oligodendrocytes: signaling without cell death in response to NGF.

Oligodendrocytes (OLs) are the primary targets in the autoimmune disease multiple sclerosis (MS). Cell receptors belonging to the tumor necrosis factor receptor (TNF-R) superfamily, such as TNF receptors and fas, are implicated in signaling the injury response of OLs. The p75 neurotrophin receptor (p75(NTR)), another member of the TNF-R superfamily, has been reported to mediate nerve growth factor (NGF)-induced apoptosis in some neural systems. To address the potential relationship between p75(NTR) signaling and OL injury, we assayed adult human OLs cultured under several different conditions for p75(NTR) and tyrosine kinase receptor trkA expression, for NGF-mediated apoptosis, and for NGF-mediated jun kinase (JNK) or nuclear factor (NF) kappaB activation. In the current study, we have found expression of p75(NTR) on cultured adult CNS-derived human OLs but not on other glial cells. TrkA was not detected on these OLs in any of the culture conditions tested. Treatment of the OLs with varying concentrations of NGF over a range of time periods resulted in no significant increase in numbers of terminal transferase (TdT)-mediated d-uridine triphosphate (UTP)-biotin nick-end labeling positive OLs, whereas significant cell death was observed using TNF-alpha. Furthermore, unlike TNF-alpha treatment, NGF treatment did not significantly activate JNK, although both TNF-alpha and NGF induced nuclear translocation of NF-kappaB. These findings contrast with the recent report of NGF-mediated apoptosis in the OLs of neonatal rats matured in vitro, which express p75(NTR) but not trkA (), and suggest that, at least in humans, p75(NTR) signaling may mediate responses other than apoptosis of OLs.

Adult↗
PubMed1998

Non-MHC-restricted cell-mediated lysis of human oligodendrocytes in vitro: relation with CD56 expression.

Oligodendrocytes and their myelin membranes are the apparent target of the autoimmune response that characterizes the human adult central nervous system-demyelinating disease multiple sclerosis. Human oligodendrocytes do not express MHC class II molecules, a requirement for MHC-restricted injury mediated by myelin-reactive CD4+ T cells, the cell type implicated in initiating the disease process. In this study we observed that human adult central nervous system-derived oligodendrocytes can be susceptible to non-MHC-restricted lysis mediated by myelin basic protein-reactive CD4+ T cell lines. Cytotoxicity was significantly greater (37 +/- 4 vs 7 +/- 3%) with cell lines in which a high proportion of cells (mean, 28 +/- 6%) expressed CD56 compared with cytotoxicity mediated by low CD56 cell lines (8 +/- 2%). High CD56 cell lines, when rested in IL-2, lost cytotoxic activity and had reduced expression of CD56 (mean, 5 +/- 2%). CD4+ T cells isolated from short term (3-day) anti-CD3/IL-2-activated mononuclear cell cultures did not express CD56 and were not cytotoxic to oligodendrocytes unless lectin was added. In contrast, an enriched population of non-T cells extracted from the same activated MNC cultures expressed CD56 as well as other NK cell-associated surface molecules and was cytotoxic. These results indicate the potential susceptibility of human oligodendrocytes to non-MHC-restricted injury mediated by both Ag-reactive and nonspecific cellular immune effector cells, with CD56 expression being a common feature of the effector cells.

Adult↗
PubMed1997

Multiple sclerosis in India: a case-control study of environmental exposures.

OBJECTIVES: To compare the rate of prior environmental exposures between Indian multiple sclerosis (MS) patients and controls in order to identify potential disease triggering factors. MATERIAL AND METHODS: A standard self-administered questionnaire regarding prior exposures was presented to 56 Indian MS patients and 147 other neural disease and healthy controls at two large medical centers in India. RESULTS: The rate of prior foreign travel, surgeries, blood transfusions, clinical chicken pox and mumps infections and exposure to cats and farm animals was not significantly different between MS patients and controls. However, clinical measles infection and dog exposure occurred significantly more often in the MS patients. CONCLUSION: These findings are consistent with but do not prove an association between prior measles infection, dog exposure and MS.

Adult↗
PubMed1996

Comparison between multiple sclerosis in India and the United States: a case-control study.

The prevalence of MS in India is low, and it is unclear whether the manifestations of the disease in India are similar to the United States. We carried out a case-control study to compare the disease in the two populations and used clinical, evoked potential, and MRI criteria to assess similarities and differences. Our results indicate that the rate of disease progression and frequency of involvement of the cerebral hemispheres, cerebellum, spinal cord, and brainstem were similar in the two populations. The visual system was more frequently involved in Indian patients. No Indian patient had a family history of MS; this suggests an environmental disease-triggering agent.

Adult↗
PubMed1987

Localization and retention of mycobacterial antigen in lymph nodes of leprosy patients.

Although leprosy, a chronic disease caused by M. leprae, primarily affects skin and peripheral nerves, pathological changes and granulomas have been observed in lymph nodes which are: (a) present in tuberculoid lymph nodes in the absence of acid-fact bacilli and (b) persistent in lepromatous patients even after prolonged treatment. We detected substantial amounts of mycobacterial antigen in 16 leprous lymph nodes using anti-BCG by the peroxidase anti-peroxidase method. The load and distribution of antigen varied along the spectrum and with the duration of treatment. Tuberculoid and long-term treated lepromatous lymph nodes had a similar distribution of antigen in clusters of cells giving a 'speckled' appearance. The untreated lepromatous had a 'diffuse' staining of antigen in foamy histiocytes whereas lepromatous lesions with a lower bacillary load had a mixed pattern of 'diffuse' and 'speckled'. Antigen was also detected in a number of plasma cells along the spectrum but predominantly in lepromatous lymph nodes. Our observations indicate that: (a) antigen exists in lymph nodes despite prolonged chemotherapy which may be responsible for the persistent granuloma and (b) antigen is not confined to any particular anatomical compartment of the lymph node.

Adolescent↗