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K D Moudgil

Publications and source records attributed to K D Moudgil.

At least 19 recordsLinked to original sources
PubMed2001

Environmental modulation of autoimmune arthritis involves the spontaneous microbial induction of T cell responses to regulatory determinants within heat shock protein 65.

Both genetic and environmental factors are believed to be involved in the induction of autoimmune diseases. Adjuvant arthritis (AA) is inducible in susceptible rat strains by injection of Mycobacterium tuberculosis, and arthritic rats raise T cell responses to the 65-kDa mycobacterial heat-shock protein (Bhsp65). We observed that Fischer 344 (F344) rats raised in a barrier facility (BF-F344) are susceptible to AA, whereas F344 rats maintained in a conventional facility (CV-F344) show significantly reduced incidence and severity of AA, despite responding well to the arthritogenic determinant within Bhsp65. The acquisition of protection from AA can be circumvented if rats are maintained on neomycin/acidified water. Strikingly, naive unimmunized CV-F344 rats but not BF-F344 rats raised T cell responses to Bhsp65 C-terminal determinants (BCTD) (we have previously shown that BCTD are involved in regulation of acute AA in the Lewis rat); however, T cells of naive CV-F344 and BF-F344 gave a comparable level of proliferative response to a mitogen, but no response at all to an irrelevant Ag. Furthermore, adoptive transfer into naive BF-F344 rats of splenic cells of naive CV-F344 rats (restimulated with BCTD in vitro) before induction of AA resulted in a considerably reduced severity of AA. These results suggest that spontaneous (inadvertent) priming of BCTD-reactive T cells, owing to determinant mimicry between Bhsp65 and its homologues in microbial agents in the conventional environment, is involved in modulating the severity of AA in CV-F344 rats. These results have important implications in broadening understanding of the host-microbe interaction in human autoimmune diseases.

Adoptive Transfer↗
PubMed2000

The self-directed T cell repertoire: its creation and activation.

The considerable breadth of the self-directed T cell repertoire has only fully been appreciated during this past decade. It is a potential repertoire which can be tapped in various ways, most evidently in the study of autoimmune diseases, when because of a variety of factors, there is enhanced processing and presentation of determinants on self antigens. In this review, we have focused on the engagement of this self-reactive repertoire and some of the rules involved, which are not always so obvious. The total "residual" self-reactive repertoire directed against a single antigen (that remains after negative selection) will be a heterogeneous assemblage of T cells - (a) high affinity T cells directed against determinants whose presentation during tolerance induction was prevented, eg. through competitive binding by neighboring determinants; (b) lower affinity T cells directed against well-presented (dominant), as well as poorly-presented (cryptic) determinants; and (c) high affinity T cells directed against poorly-presented determinants, which are only presented during inflammation. Under conditions that favor upregulation of previously cryptic self determinants, one or more of the above subsets of the 'protected' T cell repertoires can be stimulated by these self determinants, leading to induction of autoreactivity. The latter could eventually result in autoimmunity under permissive conditions governed by MHC and non-MHC genes. Interestingly, the very same repertoires that appear to be recruited into pathogenic autoimmune destruction may be alternatively manipulated as a source of anti-cancer treatment. It is now evident that many tumor antigens are unmutated self antigens, and cryptic determinants within such tumor antigens could be used to recruit the anticryptic T cell repertoire for induction of anti-tumor immunity.

Animals↗
PubMed1999

The self-directed T cell repertoire against mouse lysozyme reflects the influence of the hierarchy of its own determinants and can be engaged by a foreign lysozyme.

The T cell repertoire is shaped by the processes of positive and negative selection. We have previously shown that mice are tolerant to a native self-Ag, mouse lysozyme (ML), but they respond vigorously when challenged with different ML peptides ("cryptic" self-determinants). In this study, we have addressed the issue of the physiological significance of both the hierarchy (dominance/crypticity) of self-determinants within ML and the anti-cryptic, self (ML)-directed T cell repertoire. Our results demonstrate that there are several ML peptides that bind well to MHC but are totally nonimmunogenic when tested for proliferative T cell response and cytokine secretion: a subset of these peptides presumably represent the originally dominant self-determinants of ML, which have rendered the T cells tolerant during thymic selection. Other ML peptides, which bind well to MHC and are immunogenic, correspond to the cryptic determinants of ML: T cells against cryptic ML determinants escape tolerance induction. Thus, the mature T cell repertoire against ML bears the direct imprint of the hierarchy of self (ML)-determinants. Interestingly, hen egg white lysozyme could prime T cells in vivo that were cross-reactive with certain cryptic ML determinants, and vice versa, without requiring any coimmunization with the foreign lysozyme and ML peptide(s). Moreover, repeated, deliberate priming and expansion of T cells by hen egg white lysozyme immunization concomitantly enhanced T cell response to such cross-reactive ML determinants. This reciprocal self-foreign determinant cross-reactivity may play a previously unrecognized, but crucial, role in the expansion and diversification of self-reactive clones in the autoimmune response.

Amino Acid Sequence↗
PubMed1999

Determinant hierarchy: shaping of the self-directed T cell repertoire, and induction of autoimmunity.

The T cell determinants within a native antigen comprise the 'dominant' determinants, which are efficiently processed and presented, and the 'cryptic' determinants, which are poorly processed and presented, if at all. However, cryptic determinants can induce potent T cell responses in the peptide form. The 'subdominant' determinants lie in between these two extremes. The above hierarchy of determinants is of relevance both in defining the immunogenicity of a native antigen, and in tolerance induction to self antigens. Using the lysozyme model system, we have studied both the structural context of determinant hierarchy as well as its influence in shaping of the T cell repertoire, and in the induction of autoimmunity. In addition, we have examined the T cell response to lysozyme of individual members of hybrid F1 mouse strains. Our results demonstrate that: (a) each region within hen eggwhite lysozyme (HEL) is potentially available upon antigen processing; (b) the immunogenicity of a foreign/self antigenic determinant can be modulated by residues flanking the core determinant; (c) the hierarchy of determinants within mouse lysozyme (ML) has a significant influence on shaping of the T cell repertoire directed against this self protein; (d) the dominance/crypticity relationship of a given determinant within HEL/ML, respectively, might be of significance in the induction of autoimmunity; and (e) hybrid F1 mice show a broad heterogeneity of response to HEL in comparison to the parental strains. The results of these studies would be of significance in better understanding of the pathogenesis of human autoimmune diseases.

Amino Acid Sequence↗
PubMed1998

Heterogeneity of the T cell response to immunodominant determinants within hen eggwhite lysozyme of individual syngeneic hybrid F1 mice: implications for autoimmunity and infection.

Hybrid F1 mice derived from inbred parental mouse strains are extensively used as animal models of human autoimmune diseases and transplantation. It is generally believed that with regard to immunologic studies, hybrid F1 mice behave in a consistent manner, equivalent to any other inbred mouse strain. In this study, we report that in comparison to inbred parental strains, individual hybrid F1 mice revealed a broad heterogeneity of proliferative response to the immunodominant determinants within hen eggwhite lysozyme (HEL). Of five parental strains tested, individual mice of three strains responding to only a few dominant HEL determinants (B6, BALB/c, and B10.PL) showed quite homogeneous patterns of response, whereas two mouse strains responsive to several determinants of HEL revealed either relative homogeneity (CBA/J mice) or heterogeneity (SJL mice) of response. However, in SJL mice, responses to major, dominant determinants of HEL were quite consistent. On the contrary, regardless of the consistency of response of parental strains, all three of F1 mice [[B6 x BALB/c]F1, [B6 x CBA/J]F1, and [SJL x B10.PL]F1] revealed significantly greater heterogeneity of response, which even involved the major, dominant determinants of HEL. We attribute the above heterogeneity of response to the competitive as well as aleatory nature of the interaction between various factors, including the coexistence of different MHC (parental as well as hybrid MHC) molecules, determinant capture, and the T cell repertoire. These results have important implications for studies on autoimmunity, infection, and vaccine design in human populations, where heterozygosity is the norm rather than the exception.

Animals↗
PubMed1998

Diversification of response to hsp65 during the course of autoimmune arthritis is regulatory rather than pathogenic.

Determinant spreading has been implicated in the pathogenesis of certain autoimmune diseases in animal models. We have observed that during the course of adjuvant arthritis (AA) in the Lewis rat, there is 'diversification' of response to the bacterial 65-kDa heat shock protein (Bhsp65) towards its carboxy-terminal determinants (BCTD). Strikingly, pretreatment of naive Lewis rats with BCTD affords significant protection from AA. Our preliminary studies indicate that the diversification of response to BCTD in the Lewis rat is probably triggered in vivo by the induction and enhanced processing of self(rat) hsp65. Thus, the self hsp65-directed T-cell responses appear to be involved in mediating natural remission from acute inflammatory arthritis induced by a foreign antigen, Mycobacterium tuberculosis. This the first report describing that the new T-cell specificities arising during the course of an autoimmune disease are regulatory/protective rather than pathogenic. Moreover, our results suggest that a final common mechanism involving BCTD might be recruited by other rat strains which either are resistant to AA (WKY rats) or whose susceptibility to AA is modulated significantly by microbial flora (Fisher rats). The results of this study would contribute significantly to understanding of the pathogenesis of human rheumatoid arthritis, and in devising new therapeutic strategies for this disease.

Animals↗
PubMed1997

Immunodominance is independent of structural constraints: each region within hen eggwhite lysozyme is potentially available upon processing of native antigen.

T cell responses to different protein Ags have been shown to focus on a few ("immunodominant") determinants. We have addressed three major, interrelated questions regarding immunodominance. First, can each area within hen eggwhite lysozyme (HEL) serve as an immunodominant focus in different inbred mouse strains or are there structural constraints that limit the utilization of certain segments of the molecule? Second, in MHC-congenic mice with identical non-MHC genes, is response to HEL restricted to one or more members of a set of HEL determinants owing to processing constraints imposed by the background genes? Third, does a truncated TCR repertoire influence the immunodominance of certain determinants of HEL? Our results in 19 strains of mice, representing 11 different MHC haplotypes, demonstrate that the immunodominant determinants within HEL are distributed all over the molecule, suggesting that there is no inherent structural constraint imposed on certain regions to be always immunorecessive. However, in different mouse strains, the emergence of identical regions of HEL as immunodominant sites strictly correlates with the identity of their MHC haplotypes but not genetic background (non-MHC) genes. We attribute this relationship to "MHC-guided processing" of native Ag. Finally, our results demonstrate that a truncated TCR repertoire can result not only in the loss of response to certain immunodominant determinants, but can also result in a gain. These results should contribute significantly to further understanding of the mechanism of immunodominance.

Animals↗
PubMed1997

Diversification of T cell responses to carboxy-terminal determinants within the 65-kD heat-shock protein is involved in regulation of autoimmune arthritis.

The T cell response to the 65-kD mycobacterial heat-shock protein (Bhsp65) has been implicated in the pathogenesis of autoimmune arthritis. Adjuvant arthritis (AA) induced in the Lewis rat (RT-1(l)) by injection of Mycobacterium tuberculosis serves as an experimental model for human rheumatoid arthritis (RA). However, the immunological basis of regulation of acute AA, or of susceptibility/resistance to AA is not known. We have defined the specificity of the proliferative T cell responses to Bhsp65 during the course of AA in the Lewis rat. During the early phase of the disease (6-9 d after onset of AA), Lewis rats raised T cell responses to many determinants within Bhsp65, spread throughout the molecule. Importantly, in the late phase of the disease (8-10 wk after onset of AA), there was evidence for diversification of the T cell responses toward Bhsp65 carboxy-terminal determinants (BCTD) (namely, 417-431, 441-455, 465-479, 513-527, and 521-535). Moreover, arthritic rats in the late phase of AA also raised vigorous T cell responses to those carboxy-terminal determinants within self(rat) hsp65 (Rhsp65) that correspond in position to the above BCTD. These results suggest that the observed diversification is possibly triggered in vivo by induction of self(Rhsp65)-reactive T cells. Interestingly, another strain of rat, the Wistar Kyoto (WKY/NHsd) rat (RT-1(l)), with the same major histocompatibility complex class II molecules as the Lewis rat, was found to be resistant to AA. In WKY rats, vigorous responses to the BCTD, to which the Lewis rat responded only in the late phase of AA, were observed very early, 10 d after injection of M. tuberculosis, Strikingly, pretreatment with the peptides comprising the set of BCTD, but not its amino-terminal determinants, provided significant protection to naive Lewis rats from subsequent induction of AA. Thus, T cell responses to the BCTD are involved in regulating inflammatory arthritis in the Lewis rat and in conferring resistance to AA in the WKY rat. These results have important implications in understanding the pathogenesis of RA and in devising new immunotherapeutic strategies for this disease.

Amino Acid Sequence↗
PubMed1996

Unresponsiveness to a self-peptide of mouse lysozyme owing to hindrance of T cell receptor-major histocompatibility complex/peptide interaction caused by flanking epitopic residues.

A self-peptide containing amino acid residues 46-61 (NRGDQSTDYGIFQINSR) of mouse lysozyme (ML) (p46-61, which binds strongly to the A(k) molecule but does not bind to the E(k) molecule), can induce a strong proliferative T cell response in CBA/J mice (A[k], E[k]) but no response at all in B10.A(4R) and CBA/J mice. The critical residues within p46-59 are immunogenic in both B10.A(4R) and CBA/J mice. The critical residues within p46-61 reside between amino acid positions 51 and 59. T cells of B10.A(4R) mice primed with the truncated peptides in vivo cannot be restimulated by p46-61 in vitro. This suggests that T cell receptor (TCR) contact (epitopic) residue(s) flanking the minimal 51-59 determinant within p46-61 hinder the interaction of the p46-61/A(k) complex with the appropriate TCR(S), thereby causing a lack of proliferative T cell response in this mouse strain. Unlike B10.A(4R) mice, [B10.A(4R) x CBA/J]F1 mice responded vigorously to p46-61, suggesting that thymic APC of B10.A(4R) mice do not present a self ligand to T cells resulting in a p46-61-specific hole in the T cell repertoire in B10.A(4R) or the F1 mice. Moreover, APC from B10.A(4R) mice are capable of efficiently presenting p46-61 to peptide-specific T cell lines from CBA/J mice. The proliferative unresponsiveness of B10.A(4R) mice to p46-61 is not due to non-major histocompatibility complex genes because B10.A mice (A[k], E[k]) respond well to p46-61. Interestingly, B10.A(4R) mice can raise a good proliferative response to p46-61 (R61A) (in which the arginine residue at position 61 (R61L/F/N/K), indicating that R61 was indeed responsible for hindering the interaction of p46-61 with the appropriate TCR. Finally, chimeric mice [B10.A(4R)-->B10.A] responded vigorously to p46-61, suggesting that thymic antigen presentation environment of the B10.A mouse was critical for development of a p46-61-reactive T cell repertoire. Thus, we provide experimental demonstration of a novel mechanism for unresponsiveness to a self peptide, p46-61, in the B10.A(4R) mouse owing to hindrance: in this system it is the interaction between the available TCR and the A(k)/p46-61 complex, which is hindered by epitopic residue(s) within p46-61. We argue that besides possessing T cells that are hindered by R61 of p46-61, CBA/J and B10.A mice have developed an additional subset of T cells bearing TCRs which are not hinderable by R61, presumably through positive selection with peptides derived from class II E(k), or class I D(k)/D(d) molecules. These results have important implications in self tolerance, shaping of the T cell repertoire, and in defining susceptibility to autoimmunity.

Amino Acid Sequence↗
PubMed1996

Antigen processing and T cell repertoires as crucial aleatory features in induction of autoimmunity.

Induction of self-reactive T cell responses leading eventually to autoimmune pathology involves several key events: (1) availability of a determinant cross-reactive with the pathogenic self or foreign determinant upon processing of native antigen; the foreign molecule bearing the related determinant may have additional processing sites flanking the determinant, or at least different ones (the same determinant may only be available on the native self molecule under inflammatory conditions) (2) a T cell bearing T cell receptor (TCR) capable of response to the autoantigen; (3) ability of the processed self determinant to bind efficiently to the appropriate major histocompatibility complex (MHC) molecule as well as to interact with the appropriate TCR, coordinated with the absence of competitively dominant determinants; and (4) the lack of regulation. At any step of this cascade of interactions, the conditions could either favour induction of an autoreactive T cell response or the process may be truncated/stalled at any step without any adverse effect. A major component determining the outcome of the above interactions is the aleatory nature of the antigen processing events. Experiments highlighting these aleatory events are the focus of this report.

Animals↗
PubMed1995

Hindrance of binding to class II major histocompatibility complex molecules by a single amino acid residue contiguous to a determinant leads to crypticity of the determinant as well as lack of response to the protein antigen.

The immune system has evolved the potential to respond to a wide variety of antigens, yet unresponsiveness to many foreign determinants is encountered frequently. Here, we report a lack of response to a particular determinant, hen egg lysozyme (HEL)-(46-61)-peptide (p46-61), in C57BL/6 (H-2b) mice, whereas a strong T-cell response to this determinant is obtained in major histocompatibility complex (MHC)-identical C3H.SW mice. However, (C3H.SW x C57BL/6)F1 mice respond well to p46-61, suggesting the absence of a p46-61-specific "hole" in the T-cell repertoire in C57BL/6 mice. We further show that p46-61 cannot bind the I-Ab class II MHC molecule, whereas p46-60 lacking Arg61 exhibits good binding and is immunogenic in both strains. Thus, the presence of the hindering residue, Arg61, renders p46-61, a dominant determinant in C3H.SW, into a silent, cryptic determinant in C57BL/6 mice. Upon i.p. immunization with HEL, no T-cell responses to either HEL or p46-61 could be demonstrated in spleens of HEL-primed C57BL/6 mice, whereas a predominant response to p46-61 and HEL was demonstrated in C3H.SW mice. Evidently, C57BL/6 mice differ from C3H.SW in their ability to process p46-61 into an actual I-Ab binding determinant, indicating a putative enzymatic defect in the C57BL/6 strain. Furthermore, our results suggest that the inability of C57BL/6 mice to respond in the spleen to HEL is based upon its failure to generate a dominant immunogenic determinant from HEL, coupled with its pattern of susceptibility to regulatory effects.

Amino Acid Sequence↗
PubMed1994

The T cell repertoire against cryptic self determinants and its involvement in autoimmunity and cancer.

Developing T cells potentially directed against cryptic self determinants escape tolerance induction in the thymus and thereby enrich the T cell repertoire. Cryptic self peptides become expressed at inflammatory tissue sites which can lead to engagement of this repertoire, leading to induction and/or perpetuation of autoimmune reactivity. On the other hand, expression of cryptic self determinants on tumor cells can be useful in generating effective anti-tumor immunity. This self-directed T cell repertoire can also be activated silently to induce memory and participate unexpectedly in responses to foreign antigens and is responsible for molecular mimicry. Finally, peptides containing cryptic determinants can be utilized for peptide-based immunotherapy.

Animals↗
PubMed1993

Dominant determinants in hen eggwhite lysozyme correspond to the cryptic determinants within its self-homologue, mouse lysozyme: implications in shaping of the T cell repertoire and autoimmunity.

We have studied the mouse lysozyme (ML) peptide-specific T cell repertoire in mice of five different major histocompatibility complex (MHC) class II haplotypes. 14 ML peptides were tested in a lymph node T cell proliferation assay. Upon immunization of diverse mouse strains with native ML, there was no response to any of the ML peptides tested. However, nine peptides were immunogenic, although there was no consistent pattern of reactivity toward any peptide among these strains. Thus, an autoreactive T cell repertoire directed against cryptic self(ML)-determinants exists, and it is different in mice of different MHC haplotypes. Moreover, our results demonstrate that crypticity is MHC associated and not merely a structural attribute of the determinant. On comparison of the pattern of response of various peptides of ML and that of its foreign homologue, hen eggwhite lysozyme (HEL) in H-2k, H-2b, and H-2d strains of mice, a striking correlation was evident. The stretches of amino acid sequences of determinants within HEL that were dominant in each of these three strains, almost exactly overlapped in position with those of the cryptic ML determinants against which self-reactivity was demonstrated in the same strain. These results demonstrate that the dominance-crypticity relationship between HEL and ML resulting from differential processing of these two proteins is critical in determining the response to HEL rather than the degree of sequence difference between them. These observations have important implications in the shaping of the T cell repertoire for foreign proteins and in the pathogenesis of autoimmunity.

Amino Acid Sequence↗
PubMed1993

Homologs of Mycobacterium leprae 18-kilodalton and Mycobacterium tuberculosis 19-kilodalton antigens in other mycobacteria.

Most of the antigens of Mycobacterium leprae and M. tuberculosis that have been identified are members of stress protein families, which are highly conserved throughout many diverse species. Of the M. leprae and M. tuberculosis antigens identified by monoclonal antibodies, all except the 18-kDa M. leprae antigen and the 19-kDa M. tuberculosis antigen are strongly cross-reaction between these two species and are coded within very similar genes. Studies of T cell reactivity against mycobacterial antigens have indicated that M. tuberculosis bears epitopes that are cross-reactive with the M. leprae 18-kDa antigen, but attempts to identify an 18-kDa antigen-like protein or protein coding sequence in M. tuberculosis have been unsuccessful. We have used a combination of low-stringency DNA hybridization and polymerase chain reaction techniques to identify, isolate, and sequence genes from M. avium and M. intracellulare that are very similar to the 18-kDa antigen gene of M. leprae and others that are homologs of the 19-kDa antigen gene of M. tuberculosis. Unlike M. leprae, which contains a single 18-kDa antigen gene, M. avium and M. intracellulare each have two 18-kDa antigen coding sequences. Although the M. leprae, M. avium, and M. intracellulare 18-kDa antigen genes are all very similar to one another, as are the M. tuberculosis, M. avium, and M. intracellulare 19-kDa antigen genes, we have been unable to detect any 18-kDa antigen-like coding sequences in DNA from M. tuberculosis.

Amino Acid Sequence↗