Showing papers by "Robert L. Modlin published in 1996"

Cross-regulatory roles of interleukin (IL)-12 and IL-10 in atherosclerosis.

Abstract: T cell cytokines are known to play a major role in determining protection and pathology in infectious disease. It has recently become clear that IL-12 is a key inducer of the type 1 T cell cytokine pattern characterized by production of IFN-gamma. Conversely, IL-10 down-regulates IL-12 production and type 1 cytokine responses. We have investigated whether IL-12 and IL-10 might be involved in a chronic inflammatory reaction, atherosclerosis. In atherosclerotic plaques, we found strong expression of IFN-gamma but not IL-4 mRNAs as compared to normal arteries. IL-12 p40 mRNA and IL-12 p70 protein were also found to be abundant in atherosclerotic plaques. IL-12 was induced in monocytes in vitro in response to highly oxidized LDL but not minimally modified LDL. The cross-regulatory role of IL-10 was indicated by the expression of IL-10 in some atherosclerotic lesions, and the demonstration that exogenous rIL-10 inhibited LDL-induced IL-12 release. These data suggest that the balance between IL-12 and IL-10 production contributes to the level of immune-mediated tissue injury in atherosclerotsis.

CD1c restricts responses of mycobacteria-specific T cells. Evidence for antigen presentation by a second member of the human CD1 family.

Abstract: Previous studies suggest that CD1 is a family of Ag-presenting molecules distantly related to those encoded by the MHC. However, of the four known human CD1 proteins, only CD1b has been shown to restrict Ag-specific T cell responses. In this study, we have shown that a second member of the human CD1 family, CD1c, could also mediate Ag presentation to T cells. Three T cell lines recognizing mycobacterial Ags in a CD1c-restricted manner were isolated from normal donor blood. These T cells were MHC unrestricted, and their recognition of Ag was independent of the products of the transporter associated with Ag presentation-1/2 and DMA/B genes that are generally required for Ag presentation by MHC-encoded Ag-presenting molecules. Furthermore, unlike MHC-restricted responses to peptides, the CD1c-restricted T cell lines recognized protease-resistant mycobacterial lipid Ags. These T cell lines also showed significant cytotoxicity toward CD1c-expressing target cells even in the absence of mycobacterial Ags, which was shown by clonal analysis to be mediated by a subpopulation of T cells directly reactive to CD1c molecules. Our findings establish the ability of a second member of the CD1 family to restrict responses of Ag-specific T cells, and thus support the general hypothesis that the CD1 family comprises a third lineage of Ag-presenting molecules that presents a novel class of foreign and self Ags to MHC-unrestricted T cells.

Human Cellular Immune Responses to Mycobacterium tuberculosis

Abstract: Human infection with Mycobacterium tuberculosis results in a broad spectrum of outcomes ranging from asymptomatic infection to widespread and rapidly fatal disease. It is generally believed that this spectrum of clinical manifestations reflects a complex interaction between M. tuberculosis and human immune defenses. The immune response to tuberculosis is a double-edged sword that can contribute both to clearance of infection and tissue damage. This chapter summarizes our current understanding of human cellular immune responses to M. tuberculosis.

Evidence for a superantigen in the pathogenesis of tuberculosis.

Abstract: Tuberculosis (TB) is a disease that has posed a significant global health burden for over five thousand years [7]. In recent years the disease has made a world-wide resurgence due in large part to the increase in AIDS cases as well as the presence of multidrugresistant strains. This resurgence in TB has led to a renewed effort to understand this desease, including mechanisms of protection and pathogenesis. One approach towards understanding TB infection relies upon molecular and cellular techniques to characterize the immune response by the host to the pathogen. T cells have long been known to be pivotal to a resistance immune response. The first data supporting this position were derived from the inability of researchers to transfer immunity with serum from convalescent animals [35]. However, T cells transferred from an immune animal to a naive animal can provide protection to subsequent rechallenge. Perhaps the best evidence supporting a role for T cells in immunity to TB has been derived from gene knockout mice that fail to express major histocompatibility complex (MHC) class I or class II molecules [13, 25], and in humans, from the fact AIDS patients are exceptionally prone to infection from Mycobacterium tuberculosis [3, 11, 21, 39]. To identify T cell populations involved in the local immune response to M. tuberculosis, we decided to analyze T cells by examining the genes encoding the T cell receptor (TCR) in tuberculous pleuritis patients. These patients frequently have a large number of T cells in the pleural effusion that are antigen reactive and are actively secreting large amounts of interferon-"/(IFN-'7) [5, 6]. We reasoned that these T cells may be recognizing an immunodominant antigen that may be critical to the host for developing a successful immune response to the pathogen. To identify these T cells, we performed a TCR repertoire analysis on T cells present in the pleural fluid of tuberculous pleuritis patients, and compared these results to the repertoire