Showing papers on "Regulatory T cell published in 1996"

Oral tolerance in myelin basic protein T-cell receptor transgenic mice: suppression of autoimmune encephalomyelitis and dose-dependent induction of regulatory cells.

Abstract: Orally administered antigens induce a state of immunologic hyporesponsiveness termed oral tolerance. Different mechanisms are involved in mediating oral tolerance depending on the dose fed. Low doses of antigen generate cytokine-secreting regulatory cells, whereas high doses induce anergy or deletion. We used mice transgenic for a T-cell receptor (TCR) derived from an encephalitogenic T-cell clone specific for the acetylated N-terminal peptide of myelin basic protein (MBP) Ac-1-11 plus I-Au to test whether a regulatory T cell could be generated from the same precursor cell as that of an encephalitogenic Th1 cell and whether the induction was dose dependent. The MBP TCR transgenic mice primarily have T cells of a precursor phenotype that produce interleukin 2 (IL-2) with little interferon gamma (IFN-gamma), IL-4, or transforming growth factor beta (TGF-beta). We fed transgenic animals a low-dose (1 mg x 5) or high-dose (25 mg x 1) regimen of mouse MBP and without further immunization spleen cells were tested for cytokine production. Low-dose feeding induced prominent secretion of IL-4, IL-10, and TGF-beta, whereas minimal secretion of these cytokines was observed with high-dose feeding. Little or no change was seen in proliferation or IL-2/IFN-gamma secretion in fed animals irrespective of the dose. To demonstrate in vivo functional activity of the cytokine-secreting cells generated by oral antigen, spleen cells from low-dose-fed animals were adoptively transferred into naive (PLJ x SJL)F1 mice that were then immunized for the development of experimental autoimmune encephalomyelitis (EAE). Marked suppression of EAE was observed when T cells were transferred from MBP-fed transgenic animals but not from animals that were not fed. In contrast to oral tolerization, s.c. immunization of transgenic animals with MBP in complete Freund's adjuvant induced IFN-gamma-secreting Th1 cells in vitro and experimental encephalomyelitis in vivo. Despite the large number of cells reactive to MBP in the transgenic animals, EAE was also suppressed by low-dose feeding of MBP prior to immunization. These results demonstrate that MBP-specific T cells can differentiate in vivo into encephalitogenic or regulatory T cells depending upon the context by which they are exposed to antigen.

The Physiological Role of Regulatory T Cells in the Prevention of Autoimmunity: the Function of the Thymus in the Generation of the Regulatory T Cell Subset

Abstract: The mechanisms that mediate self/non-self discrimination among T cells are imperfectly understood but may be classified into two broad types. The first group of mechanisms are \"passive\" (or recessive) because they depend on a functional absence of autoreactive cells or the presentation of self antigens in a non-immunogenic form. The second group of mechanisms are \"active\" (or dominant) because they prevent the activation of other T cells which have the potential to cause autoimmunity. It is with these active mechanisms that this review is primarily concerned. The mechanisms of passive tolerance are generally considered to be of two types depending on the anatomical site of action: clonal deletion for those self antigens expressed intrathymically (Kappler et al. 1987) and T cell anergy (Mueller et al. 1989) or T cell indifference (Ohashi et al. 1991) for those exclusively expressed

Suppression of adjuvant arthritis in rats by induction of oral tolerance to mycobacterial 65‐kDa heat shock protein

Abstract: Oral administration of mycobacterial 65-kDa heat shock protein (HSP) given daily for 5 days prior to immunization with Mycobacterium tuberculosis (Mt) suppressed the development of adjuvant arthritis (AA) in rats. AA was significantly suppressed by 30 and 300 micrograms HSP, and variably by 0.3, 3 micrograms or 1 mg. Histological analysis of joint samples obtained from control and test rats confirmed the suppression of AA in the fed group. Feeding Mt or hen egg lysozyme (HEL) failed to affect AA, indicating that the suppression was HSP specific. The oral administration of 30 micrograms HSP decreased both delayed-type hypersensitivity (DTH) reactions and proliferative responses to HSP and Mt. In addition, the proliferation of lymph node cells (LNC) from Mt-sensitized rats was inhibited by the addition of spleen cells (SPC) from HSP-fed animals, possibly by the secretion of transforming growth factor (TGF)-beta. Spleen cells obtained from tolerized donors were capable of transferring the tolerance to naive recipients. These results demonstrate that feeding HSP is an effective way to suppress AA and that the suppression of AA may be mediated by regulatory T cells generated following oral administration of mycobacterial 65-kDa HSP.

A truncated T cell receptor repertoire reveals underlying immunogenicity of an antigenic determinant.

Abstract: Induction of T cell responses to an antigenic peptide that is known to bind a major histocompatibility complex molecule is a function of either the T cell receptor (TCR) repertoire or regulatory influences by CD8 or CD4 regulatory T cells. We have tested the hypothesis that a lack of 10 TCR V beta gene segments in V beta a mice may result in an incomplete repertoire of regulatory T cells involved in maintaining peripheral tolerance. Such a hole in the repertoire of regulatory cells could result in expression of T cell responses to antigenic determinants that normally remain undetected in mice with a wild-type repertoire of TCR V beta gene segments. We show here that H-2d mice respond to the peptide 74-96 of hen egg-white lysozyme (HEL) when they are of V beta a haplotype at their TCR locus. The wild-type (V beta b) H-2d mice with their complete set of 20 TCR V beta gene segments fail to respond to HEL 74-96. The 74-96-specific T cell responsiveness was revealed in the wild-type (V beta b) mice when they were treated in vivo with anti-CD8 antibody, implicating the existence of regulatory cells that prevent expression of T cell responses specific for peptide 74-96. This is a demonstration that holes in the regulatory T cell repertoire can, in certain circumstances, become beneficial to the host, for example, in susceptibility against pathogens.

T cell vaccination: clinical application in autoimmune diseases

Abstract: T cell responses to myelin basic protein (MBP) are implicated to play an important role in the pathogenesis of multiple sclerosis (MS). These MBP autoreactive T cells are found to undergo in vivo activation and clonal expansion in patients with MS. They accumulate in the brain compartment and may reside in the brain lesions of patients with MS. As MBP-reactive T cells potentially hold a central position in initiation and perpetuation of the brain inflammation, specific immune therapies designed to deplete them may improve the clinical course of the disease. We review here the recent application of T cell vaccination in patients with MS to deplete circulating MBP-reactive T cells. The results of our phase I clinical trial indicate that T cell vaccination with inactivated MBP autoreactive T cells induces specific regulatory T cell network of the host immune system to deplete circulating MBP-reactive T cells in a clonotype-specific fashion. The immunity induced by T cell vaccination is clonotype specific and long-lasting. Our longitudinal clinical evaluation further suggests a moderately lower rate of clinical exacerbation, disability score, and brain lesions (measured by magnetic resonance imaging) in vaccinated patients than in matched controls. Our study should encourage further investigation on the treatment efficacy of T cell vaccination and further improvement for its clinical administration in other human autoimmune diseases. This review discusses the immune regulation and therapeutic administration of T cell vaccination in human autoimmune diseases, exemplified by our recent T cell vaccination trial in MS.

Neonatal transplantation tolerance is associated with a systemic reduction in memory cells, altered chimeric cell phenotype, and modified eicosanoid and cytokine production.

Abstract: Certain B10 background mice are resistant to tolerance induction following a neonatal inoculation of semiallogeneic class I/II MHC-disparate cells despite early thymic clonal deletion of alloreactive cells The emergence of memory T cells and persistence of particular chimeric cells in the thymus has an association with this resistance In these studies, we utilized a hemisplenectomy technique to examine systemic cell populations of adult B10S (H2 s , H2E - ) mice that received (B10SxB10A)F 1 cells at birth and before and following application (and rejection or acceptance) of B10A (H2 k/d , H2E + ) skin grafts Prior to skin graft challenge, tolerant mice had reduced splenic levels of memory (CD45 hi , PgP-1 hi , Mel-14 neg ) T cells as compared with the rejecting recipients and following B10A graft challenge, the nontolerant mice showed a further increase in these cells Elevated pretransplant levels of donor H2K k + cells coexpressing B220, CD11b, or CD3 were seen in the tolerant mice Following skin grafting, splenic chimerism was reduced with differing chimeric cell phenotypes between the tolerant and nontolerant mice In vitro production of PGE 2 in a MLC was delayed in the tolerant mice with minimal production of IL-2 and IL-4 Nontolerant mice made high levels of TxB 2 and heightened, early production of IL-2 and IL-4 during the MLC Thus, tolerance induction is associated with increased numbers of particular chimeric cells, fewer peripheral lymphoid immunocompetant memory T cells, impaired eicosanoid secretion, and reduced alloreactivity and alloantigen-driven IL-2/IL-4 production It appears that alloreactive cells necessary to break tolerance are generated when fewer class II + (eg, B220 + , CD11b + ) chimeric cells are present and that there is a coexistence of effector and regulatory T cell subpopulations in the nontolerant mice By comparison, tolerance acquisition does not appear associated with the presence or generation of a predominant subtype of T cell but rather is likely more dependent upon clonal deletion processes

T cell vaccination in multiple sclerosis.

Abstract: T cell responses to myelin basic protein (MBP) are implicated to play an important role in the pathogenesis of multiple sclerosis (MS). These MBP autoreactive T cells are found to undergo in vivo activation and clonal expansion in patients with MS. They accumulate in the brain compartment and may reside in the brain lesions of patients with MS. As MBP-reactive T cells potentially hold a central position in initiation and perpetuation of the brain inflammation, specific immune therapies designed to deplete them may improve the clinical course of the disease. In this paper, the therapeutic potential of T cell vaccination in the treatment of MS is discussed in context of its immunological and clinical effect. The results of our phase one clinical trial indicate that T cell vaccination with inactivated MBP autoreactive T cells induces specific regulatory T cell network of the host immune system to deplete circulating MBP-reactive T cells in a clonotype-specific fashion. The immunity induced by T cell vaccination is clonotype-specific and long-lasting. Our longitudinal clinical evaluation further suggests a moderate reduction of rate of clinical exacerbation, disability score and the brain lesions (measured by magnetic resonance imaging) in vaccinated patients, as compared to matched controls. Our study should encourage further investigation on the treatment efficacy of T cell vaccination and further improvement for its clinical application.