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Biomedical subjects

R L Modlin

Publications and source records attributed to R L Modlin.

At least 73 records · Page 4Linked to original sources
PubMed1997

IL-15, an immunomodulator of T cell responses in intracellular infection.

IL-15 is a novel cytokine with potent T cell growth factor activity. Here, we investigated the role of IL-15 in the human immune response to intracellular infection by studying patients leprosy. We found that IL-15 mRNA and protein were more strongly expressed in immunologically resistant tuberculoid patients than in with unresponsive and susceptible lepromatous patients. In vitro, Mycobacterium leprae induced IL-15 secretion from peripheral blood monocytes. Furthermore, rIL-15 by itself and in combination with rIL-2 or rIL-7 augmented PBMC proliferative responses to the pathogen. Although rIL-15 expanded the CD3-CD56+ (NK) subset, rIL-15 combined with M. leprae induced the expansion of CD3+CD56+ T cells. Immunohistologic analysis of leprosy skin lesions indicated that the frequency of CD56+ cells was greatest in the group of patients with high IL-15 expression, and that >90% of the CD56+ cells in lesions were CD3+ T cells. Therefore, IL-15 augments the local T cell response to human intracellular pathogen.

Cytoplasm↗
PubMed1997

The mannose receptor delivers lipoglycan antigens to endosomes for presentation to T cells by CD1b molecules.

We have characterized the CD1b-mediated presentation pathway for the mycobacterial lipoglycan lipoarabinomannan (LAM) in monocyte-derived antigen-presenting cells. The macrophage mannose receptor (MR) was responsible for uptake of LAM. Antagonism of MR function inhibited both the internalization of LAM and the presentation of this antigen to LAM-reactive T cells. Intracellular MRs were most abundant in early endosomes, but they also were located in the compartment for MHC class II antigen loading (MIIC). Internalized LAM was transported to late endosomes, lysosomes, and MIICs. MRs colocalized with CD1b molecules, suggesting that the MR could deliver LAM to late endosomes for loading onto CD1b. LAM and CD1b colocalized in organelles that may be sites of lipoglycan antigen loading. This pathway links recognition of microbial antigens by a receptor of the innate immune system to the induction of adaptive T cell responses.

Antigen Presentation↗
PubMed1996

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

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.

Antigen Presentation↗
PubMed1996

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

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.

Aorta↗
PubMed1996

T-cell recognition of non-peptide antigens.

Studies of two distinct human T-cell systems have provided the exciting finding that T cells are able to recognize non-peptide antigens: gammadelta T cells have been shown to recognize isopentenyl pyrophosphate and related structures and human CD1 has been shown to present microbial lipids and lipoglycans such as mycolic acids and lipoarabinomannan to T cells. T-cell responses to these non-peptide antigens should provide a strategic target for immunologic intervention in infectious disease.

Antigen Presentation↗
PubMed1996

Interleukin-10 downregulates Mycobacterium tuberculosis-induced Th1 responses and CTLA-4 expression.

To characterize the mechanism by which interleukin 10 (IL-10) inhibits Th1 responses to intracellular pathogens, we evaluated the interaction between IL-10 and Mycobacterium tuberculosis-induced gamma interferon (IFN-gamma) production by peripheral blood mononuclear cells from persons across the spectrum of tuberculous infection. M. tuberculosis-induced IFN-gamma production was highest in healthy tuberculin reactors, intermediate in human immunodeficiency virus (HIV)-negative tuberculosis patients, and lowest in HIV-infected tuberculosis patients. Neutralizing antibodies to IL-10 increased IFN-gamma production in HIV-infected and HIV-negative tuberculosis patients by enhancing monocyte IL-12 production. Expression of the T-cell-costimulatory molecule CTLA-4 was depressed in M. tuberculosis-stimulated peripheral blood mononuclear cells from tuberculosis patients, and anti-IL-10 and Il-12 upregulated expression of CTLA-4. These findings provide evidence that intracellular pathogens can inhibit Th1 responses and downregulate expression of specific costimulatory molecules.

Abatacept↗
PubMed1995

IL-10 production in cutaneous basal and squamous cell carcinomas. A mechanism for evading the local T cell immune response.

Cytokines play a vital role in the host immune response by regulating the development and function of immunocompetent cells. To explore the possibility that tumors may alter the host response via release of immunomodulatory cytokines, we studied two different skin cancers, basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) as models. By RT-PCR, we found that the type 2 cytokines, IL-4 and IL-10, were strongly expressed in BCC compared with matched PBMC. Furthermore, IL-10 was more strongly expressed in SCC compared with benign growths. To identify the cell types responsible for production of these cytokines, tumor and tumor-infiltrating lymphocyte (TIL) cell lines were derived from BCC and SCC biopsy specimens. IL-2 and IFN-gamma mRNAs were expressed in TIL, while IL-10 mRNA were strongly expressed in BCC lines. In addition, IL-10 was detected in culture supernatants from BCC and SCC cell lines by ELISA and in tissue sections by immunohistology. TIL lines derived from these tumors demonstrated proliferative activity to autologous tumor cells in the presence of APCs, dependent on the addition of low concentrations of rIL-2 or neutralizing anti-IL-10 mAb in the culture medium. Furthermore, treatment of BCC with intralesional IFN-alpha induced tumor regression with concomitant up-regulation of IL-2 and down-regulation of IL-10 mRNA expression in lesions. These data suggest that tumor production of the cytokine, IL-10, may provide a mechanism for evading the local T cell-mediated immune response.

Basal Cell Carcinoma↗
PubMed1995

IL-7 in the cell-mediated immune response to a human pathogen.

The goal of the present study was to investigate the role of IL-7 in regulating immune responses to infection. Leprosy provides a model for understanding human immune responses to infection; the disease presents as a spectrum in which the clinical manifestations correlate with the levels of cell-mediated immunity to the pathogen, Mycobacterium leprae. To determine whether IL-7 is produced at the site of infection in leprosy, we used the PCR to measure IL-7 and IL-7R mRNA in skin lesions. IL-7 mRNA was more strongly expressed in the tuberculoid form of the disease, in which the infection is limited (mean cpm = 48 +/- 8; n = 11), as compared with the progressive lepromatous form (17 +/- 2; n = 11). IL-7R mRNA, both membrane-bound and soluble forms, were also more strongly expressed in tuberculoid lesions, although these differences were not as striking as those for IL-7. The cellular source of IL-7 included Ag-stimulated monocytes and IFN-gamma-induced keratinocytes. M. leprae-induced PBMC responses in tuberculoid patients involved up-regulation of IL-7 and IL-7R mRNA and was IL-7 dependent. In contrast, M. leprae did not induce IL-7 mRNA in lepromatous patients, and their T cell responses were weakly augmented by rIL-7. These data suggest that IL-7, produced at the site of disease, contributes to the cell-mediated immune response to human pathogens.

Base Sequence↗
PubMed1995

Multiple sclerosis: limited diversity of the V delta 2-J delta 3 T-cell receptor in chronic active lesions.

T lymphocytes bearing the gamma delta T-cell receptor have been found in the central nervous system of patients with multiple sclerosis in association with demyelinated lesions. Although the biological function of these cells remains to be established, it has been proposed that they are involved in the response to highly conserved antigens, such as heat shock proteins (hsp), expressed during tissue damage and thus may contribute to the development of an autoimmune response. Using polymerase chain reaction, we probed for the presence of T-cell receptor gamma delta cells in fresh-frozen early autopsy brain tissue from patients with multiple sclerosis and patients with non-multiple sclerosis conditions. The results demonstrated the presence of two major V-J combinations of the T-cell receptor delta chain--V delta 2-J delta 3, V delta 2-J delta 1--and we used a direct sequencing technique to determine whether this gamma delta T-cell population was clonal or diverse. In chronic-active plaques from 9 patients with multiple sclerosis, we found a striking predominant gene rearrangement within the V delta 2-J delta 3 T-cell receptor population that was not present in central nervous system tissue from patients with other neurological diseases. In contrast, within the V delta 2-J delta 1 T-cell receptor population, a predominant rearrangement pattern was detected in only 1 of the multiple sclerosis patients. The sequence of the predominant V delta 2-J delta 3 gene rearrangement was confirmed by cloning and sequencing the gene products from 1 multiple sclerosis patient.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1995

Cytokine responses in leprosy lesions.

The clinical spectrum of leprosy reflects the diverse nature of human immune responses to Mycobacterium leprae. The clinical presentations correlate with the level of cell-mediated immunity against M. leprae. Cell-mediated immunity, as assessed by the Mitsuda reaction, is positive in tuberculoid patients and negative in lepromatous patients. In contrast, humoral immunity, as assessed by anti-M. leprae antibodies is greatest in lepromatous patients. The inverse correlation between cell-mediated immunity can be explained on the basis of the local cytokine pattern.

Antibody Formation↗
PubMed1994

IL-12 regulates T helper type 1 cytokine responses in human infectious disease.

We investigated the role of IL-12 in regulating T cell and cytokine responses in human infectious disease by using the spectrum of leprosy as a model. Tuberculoid patients mount strong T cell responses to Mycobacterium leprae, with production of the type 1 cytokines IL-2 and IFN-gamma in lesions; whereas lepromatous patients manifest weak T cell responses to M. leprae, with production of the type 2 cytokines IL-4 and IL-10 in lesions. We found expression of IL-12 p40 mRNA, as measured by PCR amplification, and IL-12 p70, as measured by immunohistochemistry, to be 10-fold greater in tuberculoid lesions than in lepromatous lesions. The ability of M. leprae to stimulate release of IL-12 from monocytes was inhibited by rIL-4 and rIL-10. M. leprae-induced T cell proliferation in tuberculoid patients was blocked by the addition of neutralizing Abs to IL-12. Furthermore, rIL-12 stimulated proliferation of CD4+ type 1 T cell clones from tuberculoid lesions, but not CD8+ type 2 T cell clones from lepromatous lesions; however, both responded to rIL-2, rIL-12 augmented M. leprae-specific T cell proliferation in lepromatous patients, thereby causing the selective expansion of CD4+ T cells and increasing T cell IFN-gamma production. These data indicate that IL-12 is an important mediator in the generation of the type 1 cytokine response in human infectious disease.

Base Sequence↗
PubMed1994

Nonpeptide ligands for human gamma delta T cells.

gamma delta T cells respond to a variety of microbial pathogens and transformed cells. Their limited receptor repertoire and activation by mycobacterial antigens resistant to proteases suggest that they may recognize nonpeptide antigens. We have tested a variety of nonpeptide molecules for stimulation of human gamma delta T cells. Synthetic alkyl phosphates, particularly monoethyl phosphate (MEP), selectively activated gamma delta T cells and stimulated their proliferation in vitro. All gamma delta T cells stimulated by MEP expressed V gamma 2/V delta 2 receptors. The purified natural ligand of mycobacteria is chemically similar to, though distinct from, MEP and contains a phosphate residue that is critical for biological activity. Recognition and expansion of a specific T-cell receptor-bearing population to non-peptide ligands is unprecedented among T cells. We suggest that MEP mimics small natural ligands capable of expanding one subset of gamma delta T cells and that this recognition of nonpeptide antigens may play an important role in human immunity to pathogens.

Antibodies↗
PubMed1994

Evidence for a superantigen in human tuberculosis.

T cells are not only required for resistance to tuberculosis, but they likely contribute to the tissue damage characteristic of the disease. To define better the T cell populations that contribute to the immunopathogenesis of human tuberculosis, we investigated the T cell receptor (TCR) beta chain repertoire expressed in patients with tuberculous pleuritis. Analysis by polymerase chain reaction and flow cytometry indicated an expansion of V beta 8+ T cells at the site of disease in some donors, suggesting the possibility that Mycobacterium tuberculosis contains a superantigen. M. tuberculosis induced strong T cell proliferative responses in tuberculin-negative healthy donors in vitro, with preferential expansion of V beta 8+ T cells, independent of the CDR3 region. T cell stimulation was MHC class II-dependent and did not require antigen processing by the antigen-presenting cells. These findings are consistent with the presence of a superantigen in M. tuberculosis, aspects of which may contribute to the immunopathology of tuberculosis and to the adjuvant properties of M. tuberculosis.

Amino Acid Sequence↗