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Biomedical subjects

T B Strom

Publications and source records attributed to T B Strom.

At least 181 records · Page 10Linked to original sources
PubMed1989

Enhancement of immunosuppression by substitution of fish oil for olive oil as a vehicle for cyclosporine.

As previously reported, acute cyclosporine-induced nephrotoxicity is characterized by a decline in glomerular filtration rate and a selective intrarenal production of the vasoconstrictor thromboxane (TxA2), but not vasodilator prostaglandin E2 (PGE2), or prostacyclin (PGI2), cyclooxygenase metabolites. Fish oils (FO), that are rich in n-3 polyunsaturated fatty acids have a high affinity for cyclooxygenase but serve as poor substrate inhibit TxA2 synthesis. We have shown that when FO replaces olive oil (OO) as the vehicle for CsA, CsA-induced nephrotoxicity and increased TxA2 synthesis are obviated in rodent models. In this study, we demonstrate that the FO vehicle for CsA does not compromise CsA's immunosuppressive properties as deduced from studies of a delayed-type hypersensitivity (DTH) model in BALB/c mice and in a rat heart transplant model. In fact, concurrent FO administration with CsA actually enhances immunosuppression. A dose of CsA incapable of blunting DTH when injected in OO was suppressive when given in FO. Administration of as little as 0.05 ml of FO vehicle potentiated the suppressive action of CsA. In addition, nonconcurrent dietary supplementation of FO in animals receiving CsA caused an increase in the immunosuppressive action of CsA in DTH. FO alone reduced DTH as compared with OO, but was far less effective than CsA plus FO. Furthermore, doses of CsA (5 mg/kg/day or 1.5 mg/kg/day), which are subtherapeutic when administered with OO, prolonged engraftment of Lewis recipients of Lewis x Brown-Norway F1 hearts when CsA was solubilized with FO. These studies indicate that concurrent administration of CsA and FO potentiates the activity of CsA and thus increases its therapeutic index. Thus, CsA plus FO is potentially a safe, potent antirejection therapy worthy of clinical testing, especially insofar as FO prevents CsA-induced acute nephrotoxicity in the rodent.

Adjuvants, Immunologic↗
PubMed1989

Differential IL-2 receptor expression in renal allograft recipients treated with an anti-IL-2-receptor antibody.

Patients were entered into a randomized trial of prophylaxis for renal allograft rejection by the administration of an anti-human IL-2 receptor antibody, anti-Tac, during the first ten days posttransplant. Interleukin-2 receptor (IL-2 R) expression was measured using two anti-IL-2 R monoclonal antibodies (moAbs), anti-Tac and 1HT4-4H3. These two antibodies recognize closely spaced epitopes on the 55 kD chain of the IL-2 R. IL-2 R expression was examined on peripheral blood small lymphocytes in three groups of patients who received: (A) cyclosporine CsA and prednisone for baseline immunosuppression (n = 9); (B) anti-Tac with CsA and prednisone as baseline immunosuppression (n = 12); and (C) anti-Tac with azathioprine and prednisone as baseline immunosuppression (n = 5). We found that large numbers of T cells express IL-2 receptors despite the presence of anti-Tac (average of IL-2 R-positive cells at day of peak IL-2 R expression 56.0 +/- 20.8% in group A, 65.2 +/- 26.6% in group B, 21.0 +/- 7.4% in group C). IL-2 R expression did not correlate with clinical activity, and the presence or accessibility of epitopes on the same 55 kD chain varied dramatically from patient to patient.

Antibodies, Monoclonal↗
PubMed1989

Differential regulation of activation-associated receptor expression on CD4- and CD8-positive T lymphocytes by allosensitized suppressor T cells.

We have demonstrated by two-color flow cytometry that allosensitized human suppressor T cells thwart progression of alloactivated T cells into the G1B stage of the cell cycle, and consequently prevent the expression of transferrin receptors on the majority of alloreactive MLR responder cells (P less than 0.005). Suppressor cells inhibit transferrin as well as interleukin-2 receptor expression on both CD4- and CD8-positive responder cells. The addition of 20 U/ml of recombinant interleukin-2 at the initiation of suppressor coculture bioassays completely neutralizes the suppressive effect of suppressor T cells exerted on CD8-positive responder T cells, but does not restore expression of transferrin and interleukin-2 receptors on CD4-positive T cells. Hence, CD4-positive T cells are the direct target of the suppressor cells, while inhibition of transferrin and interleukin-2 receptor expression on CD8-positive T cells results from reduced levels of interleukin-2 in suppressor cell-regulated cultures. In suppressor cell modified mixed lymphocyte reactions supplemented with exogenous interleukin-2 CD8+/CD28- responder cells proliferate preferentially. It is apparent that mixed lymphocyte reactions supplemented with allosensitized suppressor cells cultured in an interleukin-2-rich environment create a milieu that permits the preferential expansion of T cells with suppressor effector phenotype. This in vitro system provides a convenient model in which to cultivate activated CD8+/CD28- T cells.

Antigens, Differentiation↗
PubMed1989

Recombinant human gamma interferon enhances in vitro activation of lymphocytes isolated from patients with acquired immunodeficiency syndrome.

Decreased responses to antigens and lectins are a characteristic feature of peripheral blood lymphocytes isolated from patients with the acquired immunodeficiency syndrome (AIDS). The in vitro addition of recombinant gamma interferon (IFN-gamma) to cultures of peripheral blood lymphocytes obtained from patients with AIDS resulted in an augmented proliferative response [( 3H]thymidine uptake) to phytohemagglutinin (PHA) and an enrichment in CD4+ and CD8+ T lymphocytes. In AIDS cultures stimulated with PHA, IFN-gamma increased the release of T-cell growth factors and enhanced the expression of interleukin-2 receptors on activated lymphocytes. Responsiveness to PHA was augmented, albeit to a lesser extent, by IFN-gamma in cultures derived from normal donors. Proliferation to microbial antigens including herpes simplex virus, cytomegalo virus, and Candida albicans was increased by IFN-gamma in cultures established from a group of AIDS patients with Kaposi's sarcoma who had no history of opportunistic infection.

Acquired Immunodeficiency Syndrome↗
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

Interleukin 2 receptor-targeted cytotoxicity. Interleukin 2 receptor-mediated action of a diphtheria toxin-related interleukin 2 fusion protein.

The IL-2 toxin-mediated inhibition of protein synthesis in high affinity IL-2-R-positive murine and human T cell lines has been examined. Both excess free IL-2 and mAb to the Tac epitope of the p55 subunit of IL-2-R are shown to block the action of IL-2 toxin; whereas, agents that interact with other receptors or antigens on the T cell surface have no effect. We show that IL-2 toxin, like diphtheria toxin, must pass through an acidic vesicle in order to intoxicate target T cells. Finally, we demonstrate that the IL-2 toxin-mediated inhibition of protein synthesis in both human and murine T cells that bear the high affinity IL-2-R is due to the classic diphtheria toxin fragment A-catalyzed ADP ribosylation of elongation factor 2.

ADP Ribose Transferases↗
PubMed1988

Anti-interleukin 2 receptor antibody suppresses murine diabetic insulitis and lupus nephritis.

In order to assess the importance of interleukin 2 receptor (IL-2R)-positive activated lymphocytes and macrophages in the pathogenesis of autoimmunity, we tested the prophylactic therapeutic efficacy of an anti-IL-2R (M7/20) monoclonal antibody, which recognizes the 55-kDa subunit of the heterodimeric IL-2R in two distinct models: the nonobese diabetic mouse and the NZB x NZW F1 hybrid with lupus. Treatment with anti-IL-2R monoclonal antibody suppressed autoimmune insulitis in nonobese diabetic mice and lupus nephritis in the NZB x NZW F1 hybrid. These studies indicate that highly selective targeting to activated lymphocytes and macrophages expressing the IL-2R provides a discrete method of dampening autoimmunity.

Animals↗
PubMed1988

Anti-interleukin-2 receptor monoclonal antibody therapy induces anti-idiotypic antibodies in mice that block both in vitro and in vivo activity.

Monoclonal antibodies (Mab) targeting certain T cell-surface proteins including the interleukin-2 (IL2) receptor molecule exert powerful immunosuppressive effects. A potential limiting factor to Mab therapy is the formation of neutralizing anti-idiotypic antibodies (Anti-Id). In this study, we demonstrate that an anti-IL2 receptor Mab, M7/20, when administered at doses which are immunosuppressive in vivo rapidly elicits an anti-idiotypic (anti-Id) antibody response. The induced antibodies are capable of blocking M7/20 binding to its target, the IL2 receptor, in vitro. Such anti-Id when given in concert with M7/20 block the expected in vivo inhibitory effects in delayed type hypersensitivity. Thus, mice respond to therapeutic doses of Mab therapy with the formation of neutralizing anti-Id. As this response is similar to that observed in humans given xenogeneic Mab, this model may be useful to further our understanding of this form of therapy.

Animals↗
PubMed1988

Interleukin 2 toxin: a step toward selective immunomodulation.

We have used protein engineering and recombinant DNA methodologies to genetically replace the eukaryotic cell receptor binding domain of diphtheria toxin with interleukin 2 (IL-2). The toxin-related T cell growth factor fusion gene has been cloned in Escherichia coli K12. Recombinant strains of E coli produce a 68,086 K hybrid toxin, IL-2 toxin that retains immunologic properties intrinsic to both its diphtheria toxin and IL-2 components. IL-2 toxin has been found to selectively inhibit protein synthesis in both human and murine T cell lines that bear high affinity IL-2 receptors, whereas the hybrid toxin is not active against cells that do not bear this receptor. The cytotoxic action of IL-2 toxin is specifically blocked by free IL-2 and monoclonal antibodies that bind to the p55 (Tac antigen) subunit of the high affinity IL-2 receptor. In addition, IL-2 toxin, like diphtheria toxin itself, must pass through an acidic compartment in order to deliver its adenosine diphosphate ribosyl transferase activity to the cytosol of target T cells. In a murine delayed type hypersensitivity (DTH) model system, we have shown that IL-2 toxin treatment induces a marked immunosuppression.

Adjuvants, Immunologic↗
PubMed1988

Interleukin 2-diphtheria toxin fusion protein can abolish cell-mediated immunity in vivo.

De novo expression of the interleukin 2 receptor (IL-2R) is a critical and pivotal event in initiation of an immune response. Targeting the low-affinity IL-2-binding p55 subunit of the high-affinity IL-2R with the rat anti-mouse IgM monoclonal antibody M7/20 suppresses a variety of T-cell-mediated reactions, including transplant rejection, autoimmunity, and delayed-type hypersensitivity (DTH). A hybrid IL-2-toxin gene was constructed from the diphtheria toxin gene by replacing the DNA encoding the diphtheria toxin receptor-binding domain with the DNA encoding the receptor-binding domain of IL-2, and the fusion protein encoded by the hybrid gene was expressed in Escherichia coli [Williams, D.P., Parker, K., Bacha, P., Bishai, W., Borowski, M., Genbauffe, F., Strom, T.B. & Murphy, J.R. (1987) Protein Eng. 1, 493-498]. We examined the action of the chimeric IL-2-toxin fusion protein on an in vivo T-cell mediated response, DTH. The IL-2-toxin fusion protein was found to be a potent immunosuppressive agent. Treatment of mice with the IL-2-toxin blocks DTH and prevents expansion of IL-2R+ T cells. Indeed, IL-2-toxin treatment targets IL-2R+ T cells in vivo and is shown to selectively eliminate their appearance in draining lymph nodes. DTH suppression was observed even in mice possessing high titers of antibodies to diphtheria toxoid.

Animals↗