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Biomedical subjects

T B Strom

Publications and source records attributed to T B Strom.

At least 235 records · Page 13Linked to original sources
PubMed1986

Therapy with monoclonal antibody to interleukin 2 receptor spares suppressor T cells and prevents or reverses acute allograft rejection in rats.

The mouse hybridoma ART 18 monoclonal antibody (mAb), which binds to the rat interleukin 2 (IL-2) receptor, was studied for its effect on heterotopic cardiac allograft survival in two histoincompatible inbred rat strain combinations. Treatment with ART 18 mAb for 10 days after transplantation prolonged allograft survival in a dose-dependent fashion up to about 3 weeks (acute rejection normally occurs within 8 days). ART 18 mAb therapy started at 5 days after transplantation the time of major rejection activity) abrogated acute rejection and extended the survival to about 18 days. The dense cellular infiltrate noted histologically in acute rejection had virtually disappeared after ART 18 mAb treatment. Thus, IL-2 receptor-targeted therapy can be successfully used to prevent and/or treat acute rejection. When spleen cells from antibody-treated recipients bearing well-functioning allografts were adoptively transferred to normal untreated rats that received cardiac allografts 24 hr later, the survival of donor-specific, but not third-party, test cardiac allografts was prolonged significantly; this supports the idea that ART 18 mAb induced "sparing" of suppressor T lymphocytes. Combining infusion of ART 18 mAb with exogenous IL-2-rich conditioned medium produced the same effect as if the mAb alone had been administered, suggesting that an excess of IL-2 does not prevent binding of ART 18 mAb to IL-2 receptor-bearing cells in vivo. These results support the important role of the IL-2 receptor-bearing cells in the mechanism of allograft rejection; they may represent an important target for immunosuppression in clinical organ transplantation.

Animals↗
PubMed1986

Development of suppressor lymphocytes during acute rejection of rat cardiac allografts and preservation of suppression by anti-IL-2-receptor monoclonal antibody.

Suppressor activity was investigated in rats undergoing acute rejection of heterotopic cardiac allografts. Spleen cells were harvested at 7 days from LEW rats rejecting (LEW x BN)F1 heart grafts and fractionated into their T, T suppressor/cytotoxic, and T helper subpopulations. Transfer of alloimmune unseparated spleen cells to syngeneic recipients of (Lew x BN)F1 test grafts accelerated rejection from 8 to 6.5 days (P less than 0.01). Graft survival was prolonged to about 15 days (P less than 0.005) after transfer of the splenic T suppressor/cytotoxic fraction. Treatment of test graft recipients with ART-18, a mouse antirat monoclonal antibody directed against the rat interleukin 2 receptor on the surface of activated lymphocytes, increased graft survival to about 3 weeks (P less than 0.005), and to about 23 days (P less than 0.005) when test graft recipients were treated with ART 18 following transfer of alloimmune unseparated spleen cells. In contrast, ART-18 treatment of test graft recipients already injected with T suppressor/cytotoxic cells had no additive effect. Increased production of endogenous interleukin 2 occurred concomitantly with the onset of rejection in these animals; interleukin 2 release declined during the late stages of rejection when suppressor activity had increased. Similarly, in T-cell-depleted (B) rats, allograft rejection could be produced by immune reconstitution with sensitized lymphocytes, but could be significantly delayed by prior transfer of suppressor cells. These data document the presence of potent suppressor activity in the acutely rejecting host and suggest that the suppressor mechanisms are inhibited less than effector mechanisms by interleukin-2-receptor-targeted therapy.

Animals↗
PubMed1985

Administration of an anti-interleukin 2 receptor monoclonal antibody prolongs cardiac allograft survival in mice.

Administration of the monoclonal antibody M7/20, which binds to the murine interleukin-2 (IL) receptor, significantly prolongs cardiac allograft survival in two H-2-incompatible strain combinations of inbred mice. The results support the important role of the IL-2 receptor in the mechanism of graft rejection, and suggest its suitability as a target for immunosuppressive therapy.

Animals↗
PubMed1985

The early (18-hr) human mixed lymphocyte reaction: identification and isolation of activated T-cell clones.

This study provides direct evidence that de novo expression of the activation antigens B1 49.9 (49.9) (interleukin-2 receptor) and 4F2 enables identification of alloactivated cells within 18 hr of initiation of human mixed lymphocyte reactions (MLR). Using a dual-parameter flow cytometer (simultaneous assessment of immunofluorescence and DNA content on the same cell), it was demonstrated that these activation antigens emerge before activated cells enter into S/G2/M phase of the cell cycle. Family studies illustrate that early activation antigen appearance occurs in response to a mismatch at chromosome 6, and invariably heralds the proliferative outcome at 6 days of MLR. In order to directly study the small alloactivated T-cell population, 49.9-positive cells were isolated using a cell sorter after 18 hr of MLR and cloned by limiting dilution using purified recombinant interleukin-2 (rIL-2). Antigen-specific T4-positive T-cell clones were isolated. Analysis of these clones demonstrates that antigen-specific reactivity is acquired within 18 hr in the MLR. These methods should permit a dissection of the early events of alloactivation.

Antibodies, Monoclonal↗
PubMed1985

Interleukin-2 apparently upregulates its receptor and induces proliferation of various resting mononuclear leukocytes in the absence of antigen.

We demonstrate that exposure to highly purified recombinant interleukin 2 (rIL-2) in the absence of known antigenic stimulation induces/increases the expression of two activation-associated proteins, the interleukin 2 receptor (IL-2R) and 4F2 on "resting" peripheral blood mononuclear cells (PBMC); subsequently, these cells enter the S phase of the cell cycle and proliferate. Dual parameter flow cytometry indicates that the phenotype of the cell population(s) which proliferate following this treatment includes HNK+, DR+, and T3+ cells. A twofold expansion in the number of HNK+ and DR+ cells was observed upon culturing resting PBMC in rIL-2 over a 6-day culture period. While the HNK monoclonal antibody is not specific for NK cells, these data do suggest that antigen independent growth of HNK+ cells may represent an additional mechanism by which IL-2 enhances NK effector activity, i.e., by induction of clonal growth of NK cells. In contrast, several concentrations of recombinant Interferon-gamma failed to produce a similar proliferative response.

Cell Separation↗
PubMed1985

Behavior of helper T lymphocytes in cyclosporine-mediated long-term graft acceptance in the rat.

(LEW X BN)F1 cardiac allografts are rejected acutely (7 days) in unmodified LEW rats, yet survive indefinitely following cyclosporine (CsA) treatment (15 mg/kg im for 7 days) or in T-cell-deprived (B) recipients. Using these models, the function of T helper cells (Th) in the maintenance phase of CsA-mediated long-term graft survival was examined. With monoclonal antibody immunoaffinity fractionation techniques, Th (W3/25+OX8-) were separated from spleens of CsA-treated hosts 3-4 weeks after grafting (CsA-Th), from specifically sensitized (s-Th), or from normal ungrafted (n-Th) rats. Adoptive transfer of 60 X 10(6) CsA-Th into B recipients produced rejection of donor-specific, but not third-party grafts in 21 +/- 7 days, comparable to s-Th (17 +/- 4 days), but faster than n-Th (4-5 weeks, P less than 0.025). CsA-Th recombined with T cytotoxic/suppressor phenotype (CsA-Tc/s, OX8+W3/25-) in numbers contained in 100 X 10(6) CsA-T cells were ineffectual, even when supplemented with exogenous interleukin 2-rich conditioned medium (IL-2CM); in contrast 100 X 10(6) s-T cells + IL-2CM inevitably caused acute rejection in B hosts (11 +/- 3 days). Increasing numbers of Th incrementally to 100 X 10(6) augmented the effectiveness of s-Th (rejection in 13 +/- 2 days), but did not improve potency of CsA-Th (20 +/- 2 days). Suppressor activity produced by small numbers of contaminating CsA-Tc/s (c. 0.4%, 4-5 X 10(5) cells in 100 X 10(6) CsA-Th) accounted for extended graft survival in B recipients, as this small number of CsA-Tc/s transferred into untreated syngeneic rats increased test graft survival to c. 16 days (P less than 0.001). IL-2 production by spleen cells, depressed during CsA treatment, returned to normal levels 2-3 weeks following drug withdrawal, whereas transfer of CsA-Th into B recipients induced a shift of IL-2 levels from dramatically depressed to normal, findings suggesting normal IL-2 production by CsA-Th. This report demonstrates that an unresponsive state in CsA-treated animals is achieved despite the presence of fully potent donor-specific Th. Active suppressor activity plays a critical role in the maintenance phase of graft survival in rats treated transiently with CsA.

Animals↗
PubMed1985

Characterization of a monoclonal rat anti-mouse interleukin 2 (IL-2) receptor antibody and its use in the biochemical characterization of the murine IL-2 receptor.

Anti-murine interleukin 2 (IL-2) receptor monoclonal antibodies (mAb) were made from rats immunized with murine cytotoxic lymphocytes. One mAb, designated M7/20, strongly inhibited the proliferation of both IL-2 dependent CTLL-2 cells and concanavalin A (Con A)-induced T-cell blasts. Inhibition was linearly dependent on the concentrations of both M7/20 and IL-2. Utilizing FACS analysis, M7/20 was shown to bind selectively to mitogen-activated T lymphocytes and, to a lesser degree, to activated B lymphocytes. 125I-Labeled M7/20 binding assays indicated that 48-hr Con A-induced T-cell blasts possessed 89,000 binding sites/cell with a Kd of 1.2 X 10(-9) M. Competitive binding analyses indicated that M7/20 and IL-2 occupy the same or overlapping cell surface sites. Preliminary biochemical characterization of M7/20 immunoprecipitates of detergent extracts from both surface-iodinated and internally D-[3H]glucosamine-labeled T lymphoblasts indicated that the murine IL-2 receptor is an N-glycosylated 58,000-Da glycoprotein. Together these results suggest that mAb M7/20 binds at or near the IL-2-binding epitope on the murine IL-2 receptor and, thus, upon manipulation may act as an IL-2 agonist.

Animals↗
PubMed1985

Investigation of in vivo activated T cells in multiple sclerosis and inflammatory central nervous system diseases.

Monoclonal antibodies have recently been characterized which identify activated T cells at different stages of differentiation. We compared the expression of the late appearing activation antigen defined by monoclonal antibody TS2/7 with the expression of early appearing activation antigens in a group of patients with active multiple sclerosis, encephalitis, non-inflammatory other neurologic diseases, and normal controls. An increase in TS2/7 reactivity of peripheral blood T cells was found in MS patients compared to controls (P less than 0.001), however, there was no increase in the level of early activation antigens. This was in contrast to three patients with viral encephalitis, who had an increase in the early activation antigen 4F2, but minimal, if any, increase in the TS2/7 reactive antigen. This study demonstrates that in vivo, as in vitro, it is possible to identify multiple differentiation stages for activated T cells. Furthermore, the presence of activated T cells in the peripheral blood of multiple sclerosis patients suggests that there is systemic immune activation in MS, and could provide a means to monitor abnormal immunologic activity in MS when these cells are functionally characterized.

Antibodies, Monoclonal↗
PubMed1985

Clinical experience with cyclosporine and azathioprine at Brigham and Women's Hospital.

Cyclosporine (CsA) immunosuppressive therapy of renal allograft recipients at Brigham and Women's Hospital yielded a 20% increase in 12- and 24-month allograft survival over azathioprine (Aza) treated controls. A trend towards increased allograft survival with better HLA-A,B, or DR matching in recipients of cadaver allografts treated with CsA was appreciated, but it fell short of statistical significance. Nephrotoxicity is common in CsA-treated patients and is manifested by a largely reversible increase in the serum creatinine. It is possible to convert patients from CsA to Aza without adverse effects on allograft survival or allograft function.

Adult↗
PubMed1985

Liver disease in recipients of long-functioning renal allografts.

After noting that hepatic failure was the leading cause of death in our transplant recipients whose renal allografts had functioned for more than five years, we reviewed retrospectively the post-transplant course of these patients to assess the long-term effect of liver disease in this population. Sufficient data was available to evaluate 184 of 217 long-term survivors (85%). Twenty-six patients (14%) experienced a doubling of SGOT and/or SGPT of greater than six months' duration and were defined as having chronic liver disease. The etiology of chronic liver disease was identified in 14 patients (54%), of whom 11 were HBsAg positive. Evidence of chronic hepatitis developed in only six of 26 patients (22%) during the first four years post transplant. Once enzyme abnormalities occurred, they were unremitting until death or end of the study in 73% of patients. Actuarial survival of patients with chronic liver disease was markedly decreased compared to long-surviving transplanted controls. Ten of the 12 deaths in patients with hepatocellular abnormalities were due to hepatic failure, of which eight occurred in the setting of extrahepatic sepsis. Chronic liver disease is a late complication of transplantation and is associated with significant mortality due to an increased susceptibility to overwhelming sepsis.

Adult↗
PubMed1985

Interleukin 2-dependent release of interleukin 3 activity by T4+ human T-cell clones.

We have isolated and studied two alloreactive, T4+, human lymphocyte clones that release interleukin 2 (IL-2) and interleukin 3 (IL-3) bioactivities upon stimulation with IL-2, alloantigen, or Sepharose-conjugated antibodies directed against the T3 protein. Anti-IL-2 receptor monoclonal antibodies block IL-2-, alloantigen-, or anti-T3-stimulated IL-3 release. Hence, release of IL-3 activity in each circumstance is rigorously dependent upon activation of the IL-2 receptor. Even low, nonmitogenic concentrations of recombinant IL-2 stimulated IL-3 release.

Cells, Cultured↗
PubMed1985

The effect of anti-interleukin-2 receptor monoclonal antibody on allograft rejection.

During immune response to an allograft, activated T cells express a number of cell surface activation antigens, among them the membrane receptor for the lymphokine interleukin 2 (IL-2). As the IL-2 receptor is not present on resting T cells, it offers an attractive target for potentially specific immunosuppressive therapy. The rat monoclonal antibody M7/20, which binds to the murine IL-2 receptor, was studied for its effect on allograft survival in two H-2-incompatible strain combinations in inbred mice. Treatment with M7/20 for 10 days markedly prolonged survival of vascularized, heterotopic heart allografts in both strain combinations, with indefinite graft survival in 50% of recipients. The same treatment significantly prolonged skin allograft survival in one of the two combinations. The results support the important role of the IL-2 receptor in the mechanism of graft rejection and confirm its suitability as a target for immunosuppressive therapy in transplantation.

Animals↗
PubMed1985

Phorbol myristate acetate-protein complex mimics bioactivity of human IL-1. 1. Direct evidence that PMA temporarily enters and is released from cellular compartment during superinduction protocol.

The K-562 cell line was treated with the superinduction protocol involving phorbol myristate acetate (PMA) for production of human interleukin 1 (IL-1). The resultant dialyzed K-562 superinduced supernatants contained potent IL-1-like activity when tested in 4 bioassays for IL-1. However, these K-562 SIS failed to induce fever in rabbits, the IL-1 like activity was not inhibited by an anti-human IL-1 antiserum in the murine thymocyte (LAF) assay, and the IL-1-like activity did not adhere to a specific immunoadsorbent column. Together with recent evidence that PMA may contaminate supernatants produced by the superinduction protocol and can mimic IL-1 bioactivity (9,10), the results of these novel methods suggested that IL-1 was not the bioactive moiety in K-562 SIS. To further examine the source of K-562 SIS IL-1-like activity, the active K-562 SIS were fractionated over Sephadex G-50, and the large molecular weight component (approximately 50,000) was found to express potent LAF activity yet remained nonpyrogenic. 3H-PMA was added to the superinduction protocol as a tracer for PMA migration. The 3H-PMA provided new and direct evidence that PMA adhered to or entered K-562 cells and adhered to plastic culture flasks during the serum free wash steps of the superinduction, and that PMA was released by K-562 cells into the serum containing supernatants during the incubation phase of the protocol. A 3H-PMA component of K-562 SIS co-migrated on gel filtration with the large molecular weight proteins which expressed LAF activity, and is a nondialyzable contaminant of superinduction supernatants. This PMA/protein complex is the main and perhaps the sole mediator of four distinct biological activities ascribed to IL-1.

Animals↗
PubMed1985

A fish oil diet rich in eicosapentaenoic acid reduces cyclooxygenase metabolites, and suppresses lupus in MRL-lpr mice.

Dietary supplementation of fish oil as the exclusive source of lipid suppresses autoimmune lupus in MRL-lpr mice. This marine oil diet decreases the lymphoid hyperplasia regulated by the lpr gene, prevents an increase in macrophage surface Ia expression, reduces the formation of circulating retroviral gp70 immune complexes, delays the onset of renal disease, and prolongs survival. We show that a fatty acid component uniquely present in fish oil but not in vegetable oil decreases the quantity of dienoic prostaglandin E, thromboxane B, and prostacyclin normally synthesized by multiple tissues, including kidney, lung, and macrophages, and promotes the synthesis of small amounts of trienoic prostaglandin in autoimmune mice. We suggest that this change in endogenous cyclooxygenase metabolite synthesis directly suppresses immunologic and/or inflammatory mediators of murine lupus.

Animals↗