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C B Carpenter

Publications and source records attributed to C B Carpenter.

At least 73 records · Page 4Linked to original sources
PubMed1989

Requirements for the induction of allospecific CD8+ suppressor T cells in the rat primary mixed lymphocyte response. CD4+, CD45R+ T cells, or supernatant factor.

We examined the requirements for the induction of the MLR-generated allospecific CD8+ suppressor T cells in the rat. Depleting the responder population of CD4+ T cells before initiating the primary MLR abrogates the generation of day-5 CD8+ T suppressor effectors. Readdition of at least 10% CD4+ T cells to the CD4+ depleted primary MLR reconstitutes suppressor cell generation. Using the anti-CD45R monoclonal antibody OX22, we also show that the T suppressor inducer cells are CD4+ CD45R+. Using a dual chamber Transwell culture system, which allows cells to be co-incubated without direct cell-to-cell contact, we show that a soluble factor/s, produced during the course of the primary MLR, is capable of inducing naive CD8+ T cells to become suppressor effectors but only when these CD8 T cells are in direct contact with allogeneic stimulators. Allospecificity is conferred by the stimulator cells and not by the suppressor-inducer factor. The supernatant of day-5 primary MLR is also capable of inducing antigen-specific suppressor effectors from naive CD8+ T cells, and also only in the presence of allogeneic stimulator cells. Recombinant human IL-2, in doses that are up to five times the amount present in the supernatant cultures, is unable to induce suppressor-effector cells from naive CD8+ T cells. We conclude that, to become allospecific suppressor effectors, naive CD8+ T cells require contact with allogeneic stimulator cells and either CD4+ CD45R+ suppressor inducer cells or suppressor inducer factor/s produced during the course of the primary MLR.

Animals↗
PubMed1989

Prophylactic use of monoclonal anti-IL-2 receptor antibody in cadaveric renal transplantation.

In vivo administration of an anti-interleukin-2 (anti-IL-2) receptor monoclonal antibody is a potential new therapy for prevention of allograft rejection of a freshly transplanted organ. Such an approach is more selective than targeting all T cells, or even the CD4 or CD8 major subsets, because only the very recently activated cells should be affected. A clinical trial of anti-Tac monoclonal antibody is in progress in which 20 mg of the immunoglobulin G 2a (lgG2a) antibody is administered intravenously daily for 10 days after cadaveric renal transplantation. Combinations with and without azathioprine, and with varying doses of cyclosporine with prednisone, are being evaluated in a randomized trial. Results to date show a significant immunosuppressive effect of anti-Tac, as measured by a reduced incidence and later onset of acute rejection episodes compared with cyclosporine plus prednisone or cyclosporine plus azathioprine plus prednisone. Removal or cytodestruction of IL-2-receptor positive cells from the peripheral blood does not occur to any major degree, even though serum levels of the antibody are always detectable. In addition, functional studies of MLR, CML, and suppressor cell generation 4 days after cessation of anti-Tac administration show no significant difference between treated and control groups The effect of anti-Tac seems, therefore, to be limited to inhibition of IL-2-mediated T-cell growth during the period of administration, with recovery after a few days' lag period.

Antibodies, Monoclonal↗
PubMed1989

The role of a primate model of renal transplantation in the development of new monoclonal antibodies.

In recent years, a detailed understanding of the cellular and molecular basis of the immune response has been achieved. These advances, coupled with the technology for producing monoclonal antibodies, have made possible to consider highly specific and potentially powerful methods of immunosuppressive treatment. This promise of potent and specific treatment has not been entirely fulfilled on clinical practice. A preclinical nonhuman primate model of renal transplantation is described. The model has been used to investigate two monoclonal anti-IL-2 receptor antibodies, one of which was found to be effective. Anti-Tac, an lgG2a mouse antihuman monoclonal antibody, prolongs graft survival in cynomolgus monkeys from 12 to 19 days. The role of such a model in bringing new monoclonal antibodies to the clinic is described.

Animals↗
PubMed1988

Lack of secondary suppressor response in enhanced allografted rats with endogenous suppressor activity in spleen and diminished cytotoxic T cell response.

In order to better understand the mechanisms of alloimmunization occurring in transplantation, we studied the immune response of an inbred rat strain (WF) to varied presentation of alloantigens (LEW). Hyperimmunized rats acutely reject transplanted allografts and demonstrate direct cytotoxic activity, as well as an expanded potential to generate cytotoxic and suppressor cell activity. In contrast, passively and actively enhanced animals, which exhibit allograft tolerance, demonstrate endogenous suppressor cell activity and significantly reduced potential to generate cytotoxic and suppressor cell activity. Thus, the method of immunization of the same responder strain animals with identical alloantigens will determine whether rejection or tolerance is evidenced following transplantation. The suppressor T cell activity demonstrated in the enhanced animals appears to regulate the immune response by reducing cell proliferation when challenged with alloantigen. However, when restimulated in vitro with donor cells, splenic suppressor activity declines--i.e., there is not a secondary suppressor response.

Animals↗
PubMed1987

Characterization of the Ia antigens involved in suppressor T cell generation in the rat.

The WRC rat, an intra-class II recombinant strain (RT1.B beta nB alpha aD alpha, beta a), was used to study the relative roles of the two class II loci in mixed lymphocyte reaction (MLR) proliferation and suppressor T cell (Ts) generation. Both MLR proliferation and Ts generation were noted in cultures of WRC with DA (RT1a) stimulator cells. In contrast, cultures of WRC with BN (RT1n) stimulator cells proliferate but do not generate significant amounts of Ts. The data suggest that RT1.B beta incompatibility is important in the generation of Ts in the WRC rat. Suppressor cells generated in cultures of WF (RT1u) with WRC stimulator cells potently suppressed a WF + WRCx test MLR, with less suppression when tested against either the WF + DAx or WF + BNx MLRs. The latter experiments suggest that Ts clones may be produced to either class II subregion, and therefore that MLR proliferation and Ts induction are not necessarily linked, but vary with particular genotypes. The current lack of other rat intra-class II recombinant strains precludes assignment of suppressor induction/activation to a single locus.

Animals↗
PubMed1987

Antigen specificity of mixed lymphocyte response-induced suppressor cells.

The nature of the antigens recognized by mixed lymphocyte response-generated suppressor cells is currently unknown. Previous investigations have yielded conflicting results, with different studies finding that suppressor cells recognize HLA class I antigens, class II antigens, or neither. To characterize the antigens recognized by suppressor cells (modulators) further, we generated 36 different modulators and assayed them for suppressor activity against a random 48-member HLA-typed panel in a total of 473 assays. Logistic regression analysis of the data revealed that suppression was correlated with B and DQ antigenic sharing between the original stimulator (used to generate the suppressor cells) and the test culture stimulator (p = 0.0043 and 0.0277, respectively). A role for DR antigen sharing could not be excluded. Overall, 35% of all suppressed assays could not be accounted for by the sharing of either any classical private HLA antigens, or of HLA-A or B locus cross-reactive group specificities. Suppression in these instances may involve the sharing of minor antigenic determinants, unidentified private HLA epitopes, or possibly another gene related to suppression that exists in linkage disequilibrium with the HLA-B locus or the DQ subregion.

Cross Reactions↗
PubMed1987

Differential effect of gamma-irradiated and heat-treated lymphocytes on T cell activation, and interleukin-2 and interleukin-3 release in the human mixed lymphocyte reaction.

Heat-inactivated (45 degrees C/1 hr) lymphocytes selectively activate suppressor T cells in the mixed lymphocyte reaction (MLR), while no significant proliferation and cytotoxic T lymphocyte activation can be detected. It is not well understood why hyperthermic treatment abolishes the stimulatory capacity of lymphocytes since HLA-DR molecules remain detectable immediately following heat exposure. In order to further characterize the requirements for Ts activation we studied the effects of hyperthermic treatment on cellular protein and DNA synthesis and cell surface protein expression in proliferating T and B cells; interleukin (IL)-1, IL-2, and IL-3 release following allogeneic stimulation with heat treated cells (HMLR); and IL-2 receptor expression as an indicator of T cell activation in the HMLR. Hyperthermic treatment reduced cellular protein synthesis as estimated by 14C-leucine uptake to about 15%, and DNA synthesis (3H-thymidine incorporation) to about 5% of untreated control cells. In contrast to y-irradiated cells, viability of heated cells rapidly declined within the first 24 hr. Hyperthermic treatment doubled binding of mouse immunoglobulin paralleled by an increased expression of IL-2 and transferrin receptors, while expression of HLA-DR and 4F2 proteins appeared unchanged. Stimulation with heated cells triggered the release of IL-1- and an IL-3-like bioactivity but did not induce IL-2 synthesis and/or release, thus explaining the lack of proliferation in the HMLR. Addition of exogenous IL-2 but not IL-1 restored HMLR proliferation. A comparison of allostimulation with y-irradiated and heat-treated cells revealed that significantly fewer T cells were induced to express IL-2 receptors at day 3 (14% vs. 8%, P less than 0.001) and at day 6 (42% vs. 21%, P less than 0.05) with heat-inactivated stimulators. We conclude that metabolically compromised lymphocytes activate Ts and are sufficient to stimulate IL-1 and IL-3 synthesis but do not transmit an unknown signal required for the activation of IL-2 synthesis and IL-2 receptor expression on a yet-to-be-defined T cell subset.

DNA↗
PubMed1986

Systemic natural killer activity following cardiac engraftment in the rat: lack of correlation with graft survival.

The systemic NK activity was studied both in untreated rats which acutely reject allogeneic heterotopic heart grafts and in cyclosporine-treated rats which tolerate their transplants. The trend and magnitude of changes in NK activity were similar at all time points for the two animal groups. Compared to naive rats, peak NK activity was noted 7-8 days after engraftment in untreated rats and 7-12 days after engraftment in cyclosporine-treated hosts. In both groups, NK activity returned to normal levels by 3 weeks. No evidence could be found for inactivation of NK cells or their precursors in vivo in ungrafted rats undergoing cyclosporine treatment alone. These data are consistent with prior studies and suggest that non-specific cytotoxic activity does not represent a crucial force contributing to acute rejection of vascularized organ grafts.

Animals↗