PubMed Health⌕ Search

Biomedical subjects

H Pope

Publications and source records attributed to H Pope.

At least 19 recordsLinked to original sources
PubMed1996

The nature of cryptic epitopes within the self-antigen myelin basic protein.

Mechanisms that allow potentially autoreactive T cells to escape central tolerance and persist in the peripheral lymphoid organs of healthy individuals are poorly defined. It has been proposed that such cells are specific for epitopes which normally are not well presented to the immune system or, in other words, are cryptic. We have used synthetic peptides to define potential T cell epitopes within the N-terminal portion of myelin basic protein (MBP). These were defined in terms of their relative affinity for the MHC-restriction element I-Au and their ability to activate T cells in mice of the H-2(u) haplotype. Three epitopes were identified, one of which corresponded to the known dominant N-terminal epitope (Ac1-9). The other two epitopes (9-20 and 5-20) bound to their MHC-restriction element with relatively high affinity but were cryptic, as defined by the poor response to these epitopes following immunization with intact MBP. Even the longer of these two epitopes did not induce autoimmune encephalomyelitis in H-2(u) mice. These results demonstrate that antigen processing can control both the induction of and effector function of autoreactive T cells, and is therefore a principal mechanism involved in limiting the autoreactive T cell repertoire.

Amino Acid Sequence↗
PubMed1995

The effect of aglycosylation on the immunogenicity of a humanized therapeutic CD3 monoclonal antibody.

The factors affecting the immunogenicity of a humanized gamma 1 CD3 monoclonal antibody (mAb) were investigated in transgenic mice that express the human CD3 antigen epsilon polypeptide (the mAb target antigen). Two derivatives of the mAb were employed, one with a normal, glycosylated Fc region (gamma 1 CD3 mAb), and the other with an aglycosylated Fc region (aglycosyl gamma 1 CD3 mAb). Comparisons of the antiglobulin responses elicited by the two derivatives in transgenic and nontransgenic mice demonstrated that Fab-mediated cell binding activity, dependent on target antigen expression, was a major positive determinant of CD3 mAb immunogenicity. A second positive factor was mAb Fc region glycosylation. At low dose levels the gamma 1 CD3 mAb consistently produced a higher antiglobulin response than the aglycosyl gamma 1 CD3 mAb. This was probably a result of the nonspecific, in vivo T cell activating property of the gamma 1 CD3 mAb, a consequence of its ability to cross-link T cells to Fc gamma receptor-bearing cells. (The aglycosyl gamma 1 CD3 mAb has a reduced Fc binding affinity for Fc gamma receptors and so does not activate T cells in vivo.) In support of this hypothesis, the gamma 1 CD3 mAb was able to nonspecifically enhance humoral immunity to an unrelated, coadministered antigen, whereas the aglycosyl gamma 1 CD3 mAb was not. The lower immunogenicity of the aglycosyl gamma 1 CD3 mAb correlated with a longer in vivo half-life and an improved capacity to block the target CD3 antigen. These results suggest that, as well as reducing the cytokine-induced side effects normally associated with CD3 mAb therapy, the nonactivating aglycosyl gamma 1 CD3 mAb will be less likely than the activating gamma 1 CD3 mAb to stimulate a neutralizing antiglobulin response.

Animals↗
PubMed1993

"Infectious" transplantation tolerance.

The maintenance of transplantation tolerance induced in adult mice after short-term treatment with nonlytic monoclonal antibodies to CD4 and CD8 was investigated. CD4+ T cells from tolerant mice disabled naïve lymphocytes so that they too could not reject the graft. The naïve lymphocytes that had been so disabled also became tolerant and, in turn, developed the capacity to specifically disable other naïve lymphocytes. This process of "infectious" tolerance explains why no further immunosuppression was needed to maintain long-term transplantation tolerance.

Animals↗
PubMed1993

The generation of a humanized, non-mitogenic CD3 monoclonal antibody which retains in vitro immunosuppressive properties.

CD3 antibodies are proven immunosuppressants capable of reversing transplant rejection episodes. Their general application has been limited both by their immunogenicity and, in particular, by the "first-dose" cytokine-release syndrome experienced by patients after the initial administration of antibody. We have produced a set of variants of the humanized YTH 12.5 CD3 monoclonal antibody (mAb) (Routledge et al., Eur. J. Immunol. 1991. 21: 2717) bearing different human heavy (H) chain constant regions, with the intention of finding a form of the antibody that is not able to activate T cells. Comparison of the variants having gamma 1, gamma 2, gamma 3 and gamma 4 H chains in a competitive binding assay showed that antibody avidity was not affected by IgG subclass. Using a sensitive indicator of FcR binding activity (the capacity of the CD3 mAb to redirect cytotoxic T cells to kill the monocytic cell line U-937) we demonstrated a functional hierarchy of gamma 1 = gamma 4 > alpha 2 =/> gamma 3 mb >> gamma 2. An aglycosyl version of the gamma 1 CD3 mAb, produced by site-directed mutagenesis (Asn297 to Ala), still had considerable activity in this assay (intermediate to the gamma 1 and alpha 2 CD3 mAb), albeit at a level approximately 10-fold lower than that of the parental gamma 1 form. When we tested their ability to stimulate T cell proliferation in vitro in the presence of 5% human serum, all of the wild-type immunoglobulin isotypes were found to be active, although there were T cell donor-dependent variations in the extent of the responses. The aglycosyl gamma 1 mAb was, however, completely non-mitogenic in all of ten donors tested, unless the assay was performed in IgG-free medium. Despite being non-stimulatory, this mAb was also able to inhibit the mixed lymphocyte reaction responses of both naive and primed T cells. Comparison of the gamma 1 and aglycosyl gamma 1 mAb in an experimental mouse model for CD3 mAb-induced cytokine release indicated that removal of the carbohydrate moiety from the gamma 1 constant region reduced the in vivo tumor necrosis factor-alpha response by a factor of at least 16-fold. These data suggest that the aglycosyl gamma 1 CD3 mAb is a promising candidate for immunosuppressive therapy without "first dose" side effects.

Animals↗
PubMed1991

Location and well-being among retired men.

Data from a national sample of retired men aged 60 to 74 enabled the exploration of the influence of a diverse set of variables on well-being. Findings include: (a) location produces differences in well-being, with retired men living in suburbs having the highest mean well-being scores; (b) poor health reduces the well-being of retired men in the suburbs to a greater extent than in the central cities; and (c) suburban location also indirectly influences well-being by way of its effect on informal activities.

Aged↗
PubMed1977

Can B-cell tolerance be induced by oligovalent thymus dependent antigens?

Spleen cells from adult mice were rendered "tolerant" to TNP by exposing cells in vitro to large concentrations of TNP10BSA. After such treatment the residual response to TNP was measured using TNP-LPS as antigen in vitro or in vivo. The "tolerance" observed in this system was not reversed by treating the cells with trypsin, nor by using non-specific polyclonal activators. Furthermore, responsiveness to TNP-LPS in vitro was not substantially restored when such "tolerant" cells were "parked" in vivo for 7 days. In contrast when TNP-KLH was the antigen used to challenge TNP-BSA treated cells, no unresponsiveness was observed. The results are discussed in terms of the degree of thymus dependence of the challenge antigens; subpopulations of B cells, and current hypotheses of B-cell activation;

Animals↗
PubMed1977

Co-operation across histocompatibility differences. The role of inhibitory T cells in preventing successful T-B interaction.

The efficiency of interaction of helper T cells with memory B cells of varying histocompatibility types has been studied in an in vitro microculture system. Such studies show that I-A region matching does not necessarily determine that efficient co-operation will take place. Failure to co-operate under circumstances where T and B cells match in I-A can be attributed to radiosensitive suppressor T cells. The nature of the gene differences which provoke the activity of such suppressor cells have also been examined, and it would seem that even single S.D. differences in the MHC are sufficient to generate 'suppressor' T-cell activity.

Animals↗
PubMed1977

The influence of antigen presentation on the generation of T-helper cells with different functions.

Thymocytes adoptively transferred into syngeneic irradiated recipients can be primed with antigen (KLH) to generate two types of helper function termed 'specific' and 'non-specific'. Low doses of KLH given without adjuvant generate high levels of non-specific compared to 'specific' helper T cells. Large doses of KLH given in adjuvant (FCA) generate high levels of both types of helper T cell. Explantations for this observation are discussed.

Animals↗
PubMed1976

Cooperation across the histocompatibility barrier: H2d T cells primed to antigen in an H-2d environment can cooperate with H-2k B cells.

H-2d spleen cells derived from either tetraparental or semiallogeneic radiation bone marrow chimeras can be primed to antigen within H-2d recipients to generate helper T cells capable of cooperating in a secondary response with equal efficiency with H-2d or H-2k B cells. Thus it would seem that the cooperative act between T and B cells does not require that the T cell interacts with its target B cells by either cell interaction genes or via an altered self mechanism involving both antigen and the target B-cell I-region products. This does not preclude a requirement for associative recognition or altered self in the interaction of helper T cells with accessory cells.

Animals↗
PubMed1976

Limiting dilution analysis of helper T-cell function. II. An approach to the study of the function of single helper T cells.

Procedures have been described which are suitable for experiments utilizing a microculture system whereby one can easily study the function of single helper T cells. These are: (a) the elimination of the background anti-hapten response by preliminary anti-theta + guinea-pig complement complement treatment of the 'hapten-primed' population; (b) the removal of any contaminating hapten-specific B cells from the carrier-primed population by passage through nylon wool; (c) irradiation of long-term primed 'nylon wool' enriched helper cells tp prevent cell division; (d) the partition of individual helper cells by limiting dilution.

Animals↗