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Biomedical subjects

G Gammon

Publications and source records attributed to G Gammon.

26 records · Page 2Linked to original sources
PubMed1990

T cell dominance and the vaccine problem: modifying effects on immunogenicity by residues at a distance from the site of T cell recognition.

The design of the optimal T cell-inducing component of a vaccine requires consideration of events both at, and distant from, the T cell recognition site. This area is approached here by analysis of T cell immunodominance. After describing the unpredictability of defining dominant T cell-inducing determinants and the preference of empirical methods, the question of designing a solely T determinant vaccine is explored. In this regard, evidence is presented that T helper cell-inducing and T proliferation-inducing determinants are not necessarily identical. With regard to the influence of other determinants on the molecule, three issues are discussed with relevance to vaccine design: (1) 'preferential partnerships' between T and B cells of certain specificities (2) the existence of suppressor T cells, reactive against non-overlapping determinants (3) competitive antigenic determinants, restricted to the same or to a different MHC molecule.

Animals↗
PubMed1989

How some T cells escape tolerance induction.

A feature common to many animal models of autoimmune disease, for example, experimental allergic encephalomyelitis, experimental autoimmune myasthenia gravis and collagen-induced arthritis, is the presence of self-reactive T cells in healthy animals, which are activated to produce disease by immunization with exogenous antigen. It is unclear why these T cells are not deleted during ontogeny in the thymus and, having escaped tolerance induction, why they are not spontaneously activated by self-antigen. To investigate these questions, we have examined an experimental model in which mice are tolerant to an antigen despite the presence of antigen-reactive T cells. We find that the T cells that escape tolerance induction are specific for minor determinants on the antigen. We propose that these T cells evade tolerance induction because some minor determinants are only available in relatively low amounts after in vivo processing of the whole antigen. For the same reason, these T cells are not normally activated but can be stimulated under special circumstances to circumvent tolerance.

Animals↗
PubMed1989

Central versus peripheral tolerance: clonal inactivation versus suppressor T cells, the second half of the 'Thirty Years War'.

The period of intellectual history of immunology that we wish to treat began some 30 years ago, in 1958, when the features of immune tolerance had already been described (Billingham, Brent & Medawar, 1953), but mechanisms remained difficult to fathom. The subsequent 30 years in quest of the key(s) to tolerance can be roughly divided into the pre-T-cell suppression half, and the years from 1973 to 1988 in which the major rival to ideas of clonal deletion or abortion has been the T-suppressor cell.

Animals↗
PubMed1986

Ia molecule-associated selectivity in T cell recognition of a 23-amino-acid peptide of lysozyme.

Ak- or Ek-restricted T cells, generated by immunization with a 23-amino-acid peptide of hen egg-white lysozyme (amino acid 74-96), showed a strict correlation between the minimal peptide determinant recognized and the Ia molecule restricting recognition. All Ak-restricted clones obtained from six independently derived lines recognized determinants contained within peptides 74-86, while Ek-restricted clones recognized determinants within 85-96. This correlation was true whether B10.A mice (Ak, Ek) were immunized with peptide 74-96 or with each of the two smaller peptides (74-86 or 85-96). Furthermore, a T cell response could be obtained to peptide 74-86, but not to peptide 85-96 in B10.A (4R) mice, which express only the Ak molecule. Thus, an Ia molecule-associated selectivity exists in the choice of T cell determinants even within this small 23-amino-acid peptide antigen. Significant differences were noted, however, in the boundaries of the minimal peptide determinants recognized within peptide 74-96 by Ak- or Ek-restricted T cells, in comparison to those recognized by Ab-restricted T cells. These results indicate that interaction of the same peptide with distinct Ia molecules results in recognition of unique aspects of the antigenic determinants by the T cell receptor.

Animals↗
PubMed1986

The choice between two distinct T cell determinants within a 23-amino acid region of lysozyme depends on their structural context.

The specificity of C57BL/6 T cells reactive to peptide aa 74-96 of hen egg-white lysozyme (HEL) was analyzed by using a panel of synthetic peptides of varying lengths from this region. It was found that peptide 74-96-reactive T cells induced by native HEL (aa 1-129) or its denatured fragment L2 (aa 13-105) recognized two distinct but overlapping determinants contained within aa 74-90 or aa 81-96, respectively. Peptide 74-96 itself induced both peptide 74-90-and peptide 81-96-specific T cells. Thus, a choice was made between these two potential T cell determinants on peptide 74-96, depending on which immunogen was used. Interestingly, the ability of both peptide determinants aa 74-90 and aa 81-96 to stimulate peptide 74-96-reactive T cells was partly dependent on the presence of residues within the overlap region (aa 81-90), suggesting that this region may play an important role in Iab-restricted T cell activation. This was further supported by the poor immunogenicity of shorter peptides 74-86 or 85-96, lacking residues from the overlap region in B6 mice. These two short peptides were nevertheless capable of eliciting T cell responses in B10.A mice, suggesting that the importance of this overlap region in obtaining a response to peptide 74-96 is related to the MHC haplotype.

Amino Acid Sequence↗
PubMedDate not supplied

Neonatal T-cell tolerance to minimal immunogenic peptides is caused by clonal inactivation.

The mechanisms underlying T-lymphocyte tolerance induced in neonatal mice are still unknown. It is unclear whether the tolerant state is the result of inactivation of T cells on exposure to antigen during development or of active suppression by other T cells specific for the same antigen. To distinguish between these two hypotheses, we have analysed the specificity of tolerance to three cytochrome peptides which differ by only a single amino-acid substitution in the epitope recognized by proliferative T cells. The peptides stimulate proliferative responses which are highly specific with minimal cross-reactivity. As antigen-induced clonal inactivation would address the same cells normally activated by that antigen, the specificity of tolerance should exactly match that of the proliferative response to the antigen, and each cytochrome peptide should induce tolerance to itself alone. Conversely, as T-suppressor (Ts) and T-proliferative (Tp) cells almost invariably seem to recognize distinct, non-overlapping determinants on protein antigens, suppressor-mediated tolerance should not be affected by substitutions in the proliferative T-cell epitope. Tolerance would depend solely on the existence of a shared suppressor determinant, so each cytochrome peptide should induce cross-tolerance to the others. We found that the specificity of tolerance matched that of the proliferative response: each peptide induced tolerance for itself but the response to the variants was unaltered. This result strongly supports the hypothesis of clonal inactivation as an important mechanism in induction of neonatal tolerance.

Animals↗