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T B Strom

Publications and source records attributed to T B Strom.

At least 37 records · Page 2Linked to original sources
PubMed2000

Prospects and applicability of molecular diagnosis of allograft rejection.

We believe that changes in blood urea nitrogen and plasma creatinine are, at best, surrogate markers for rejection. It seems certain that rejection, an immunologic process must precede deterioration in renal function. We suggest that the efforts to prevent chronic rejection should include an effective means to diagnose rejection before the advent of fixed renal injury. Through an analysis of transcription for a series of genes that are expressed by activated, but not resting, cytotoxic lymphocytes, eg, granzyme B, a remarkably accurate tool for assessing the presence of rejection has emerged. Although our methods first centered on analysis of kidney transplant biopsy specimens, noninvasive surveillance using transcriptional profiling analysis circulating blood or urine sediment cells has proven equally informative.

Animals↗
PubMed1999

IL-10/Fc inhibits macrophage function and prolongs pancreatic islet xenograft survival.

BACKGROUND: Xenograft rejection is a complex response in which macrophages and other effector cells are activated by CD4+ T cells. Initiation and regulation of this response is in part mediated by cytokines. In this study we test the hypothesis that xenograft destruction is an interleukin- (IL) 10 responsive, macrophage-mediated event. METHODS: To study the effect of the systemic administration of IL-10 on pancreatic islet xenograft rejection, a fusion protein of IL-10/Fc was used. This immunoligand possesses the bioavailability of IL-10 and the long circulating t1/2 in vivo, characteristic of Ig. Wistar rat islets were transplanted into C57BL6 mice. IL-10/Fc was administered either immediately before transplantation or in the posttransplant period. RESULTS: Both therapeutic protocols prolonged xenograft survival. Macrophage effector function was reduced in IL-10/Fc-treated mice, with a reduced macrophage infiltrate, reduced IL-12 and tumor necrosis factor-alpha gene expression and reduced serum NO2- levels. Although the number of T cells infiltrating islet grafts was not reduced, T cell effector function was inhibited in IL-10/Fc-treated animals with reduced interferon-gamma and IL-4 gene expression, reduced anti-donor cytotoxicity by recipient splenocytes and reduced anti-donor IgG1 antibody production. Ultimate rejection of the xenografts appears to be mediated by a CD4+ T cell dependent mechanism probably as a result of inadequate inhibition of IL-12 production by macrophages. CONCLUSION: IL-10/Fc prolonged rat pancreatic islet xenograft survival by inhibiting macrophage mediated immune responses. The effectiveness of this agent when administered pretransplant suggests it may have a role as an induction agent with potential clinical application.

Animals↗
PubMed1999

Antigen-induced unresponsiveness results in altered T cell signaling.

Pretransplant exposure to allogeneic lymphocytes can result in donor-specific unresponsiveness and prolonged allograft survival. Intracellular signaling events have been described in anergic T cell clones, but the biochemical events underlying in vivo induced unresponsiveness have not been studied in detail. We employed a TCR transgenic mouse, bearing the 2C TCR, providing adequate numbers of homogenous peripheral T cells to study biochemical aspects of T cell unresponsiveness in vivo. 2C mice exposed to semiallogeneic lymphocytes (H-2b x H-2d) experienced prolonged H-2d cardiac allograft survival, and cells from these mice did not proliferate or make IL-2 in response to alloantigen (H-2d). Importantly, there were marked differences in TCR-associated tyrosine phosphorylation activation patterns. The targets for the unresponsive state appear to be diminished Lck activation and absent ZAP-70 and LAT (linker for activation of T cells) phosphorylation. Our study demonstrates that Ag-induced tolerance in vivo is accompanied by altered early TCR-mediated signaling events.

Animals↗
PubMed1999

IL-2 receptor-targeted cytolytic IL-2/Fc fusion protein treatment blocks diabetogenic autoimmunity in nonobese diabetic mice.

High affinity IL-2R5 is present on recently activated but not on resting or memory T cells. Selective targeting of T cells bearing high affinity IL-2R is an attractive therapy for many T cell-dependent cytopathic disease processes. A variety of rodent mAbs directed against the alpha-chain of the IL-2R, as well as IL-2 fusion toxins, have been used in animals and humans to achieve selective immunosuppression. Here we report on the development of a novel IL-2R targeting agent, a cytolytic chimeric IL-2/Fc fusion protein. This immunoligand binds specifically and with high affinity to IL-2R and is structurally capable of recruiting host Ab-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity activities. The Ig component ensures an extended circulating t1/2 of 25 h following systemic administration. To subsequently explore the mechanisms of the antidiabetogenic effects of IL-2/Fc, we have mutated the FcR binding and complement C1q binding (Fc-/-) domains of the Fc fragment to render the Fc unable to direct Ab-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity activities. In a model of passive transfer of diabetes in nonobese diabetic mice, lytic IL-2/Fc, but not nonlytic IL-2/Fc-/-, exhibited striking antidiabetogenic effects. Together with the negligible potential of IL-2/Fc for immunogenicity, this finding forecasts that cytolytic IL-2/Fc may offer a new therapeutic approach for selective targeting of auto and alloimmune T cells.

Adoptive Transfer↗
PubMed1999

Induction of allograft tolerance in the absence of Fas-mediated apoptosis.

Using certain immunosuppressive regimens, IL-2 knockout (KO) mice, in contrast to wild-type (wt) controls, are resistant to the induction of allograft tolerance. The mechanism by which IL-2 regulates allograft tolerance is uncertain. As IL-2 KO mice have a profound defect in Fas-mediated apoptosis, we hypothesized that Fas-mediated apoptosis of alloreactive T cells may be critical in the acquisition of allograft tolerance. To definitively study the role of Fas in the induction of transplantation tolerance, we used Fas mutant B6.MRL-lpr mice as allograft recipients of islet and vascularized cardiac transplants. Alloantigen-stimulated proliferation and apoptosis of Fas-deficient cells were also studied in vivo. Fas mutant B6.MRL-lpr (H-2b) mice rapidly rejected fully MHC-mismatched DBA/2 (H-2d) islet allografts and vascularized cardiac allografts with a tempo that is comparable to wt control mice. Both wt and B6.MRL-lpr mice transplanted with fully MHC-mismatched islet allografts or cardiac allografts can be readily tolerized by either rapamycin or combined costimulation blockade (CTLA-4Ig plus anti-CD40L mAb). Despite the profound defect of Fas-mediated apoptosis, Fas-deficient T cells can still undergo apoptotic cell death in vivo in response to alloantigen stimulation. Our study suggests that: 1) Fas is not necessarily essential for allograft tolerance, and 2) Fas-mediated apoptosis is not central to the IL-2-dependent mechanism governing the acquisition of allograft tolerance.

Animals↗
PubMed1999

CTLA4 signals are required to optimally induce allograft tolerance with combined donor-specific transfusion and anti-CD154 monoclonal antibody treatment.

Sensitization to donor Ags is an enormous problem in clinical transplantation. In an islet allograft model, presensitization of recipients through donor-specific transfusion (DST) 4 wk before transplantation results in accelerated rejection. We demonstrate that combined DST with anti-CD154 (CD40L) therapy not only prevents the deleterious presensitization produced by pretransplant DST in the islet allograft model, it also induces broad alloantigen-specific tolerance and permits subsequent engraftment of donor islet or cardiac grafts without further treatment. In addition, our data strongly indicate that CTLA4-negative T cell signals are required to achieve prolonged engraftment of skin allograft or tolerance to islet allograft in recipients treated with a combination of pretransplant DST and anti-CD154 mAb. We provide direct evidence that a CD28-independent CTLA4 signal delivers a strong negative signal to CD4+ T cells that can block alloimmune MLR responses. In this study immune deviation into a Th2 (IL-4) response was associated with, but did not insure, graft tolerance, as the inopportune timing of B7 blockade with CTLA4/Ig therapy prevented uniform tolerance but did not prevent Th2-type immune deviation. While CTLA4-negative signals are necessary for tolerance induction, Th1 to Th2 immune deviation cannot be sufficient for tolerance induction. Combined pretransplant DST with anti-CD154 mAb treatment may be attractive for clinical deployment, and strategies aimed to selectively block CD28 without interrupting CTLA4/B7 interaction might prove highly effective in the induction of tolerance.

Abatacept↗
PubMed1999

Blocking both signal 1 and signal 2 of T-cell activation prevents apoptosis of alloreactive T cells and induction of peripheral allograft tolerance.

The alloimmune response against fully MHC-mismatched allografts, compared with immune responses to nominal antigens, entails an unusually large clonal size of alloreactive T cells. Thus, induction of peripheral allograft tolerance established in the absence of immune system ablation and reconstitution is a challenging task in transplantation. Here, we determined whether a reduction in the mass of alloreactive T cells due to apoptosis is an essential initial step for induction of stable allograft tolerance with non-lymphoablative therapy. Blocking both CD28-B7 and CD40-CD40 ligand interactions (co-stimulation blockade) inhibited proliferation of alloreactive T cells in vivo while allowing cell cycle-dependent T-cell apoptosis of proliferating T cells, with permanent engraftment of cardiac allografts but not skin allografts. Treatment with rapamycin plus co-stimulation blockade resulted in massive apoptosis of alloreactive T cells and produced stable skin allograft tolerance, a very stringent test of allograft tolerance. In contrast, treatment with cyclosporine A and co-stimulation blockade abolished T-cell proliferation and apoptosis, as well as the induction of stable allograft tolerance. Our data indicate that induction of T-cell apoptosis and peripheral allograft tolerance is prevented by blocking both signal 1 and signal 2 of T-cell activation.

Adaptation, Physiological↗
PubMed1999

Requirement for T-cell apoptosis in the induction of peripheral transplantation tolerance.

The mechanisms of allograft tolerance have been classified as deletion, anergy, ignorance and suppression/regulation. Deletion has been implicated in central tolerance, whereas peripheral tolerance has generally been ascribed to clonal anergy and/or active immunoregulatory states. Here, we used two distinct systems to assess the requirement for T-cell deletion in peripheral tolerance induction. In mice transgenic for Bcl-xL, T cells were resistant to passive cell death through cytokine withdrawal, whereas T cells from interleukin-2-deficient mice did not undergo activation-induced cell death. Using either agents that block co-stimulatory pathways or the immunosuppressive drug rapamycin, which we have shown here blocks the proliferative component of interleukin-2 signaling but does not inhibit priming for activation-induced cell death, we found that mice with defective passive or active T-cell apoptotic pathways were resistant to induction of transplantation tolerance. Thus, deletion of activated T cells through activation-induced cell death or growth factor withdrawal seems necessary to achieve peripheral tolerance across major histocompatibility complex barriers.

Abatacept↗
PubMed1998

Combined costimulation blockade plus rapamycin but not cyclosporine produces permanent engraftment.

BACKGROUND: Combined treatment of allograft recipients with anti-CD40 ligand and CTLA-4Ig (costimulation blockade) is a powerful promising albeit not consistently tolerizing therapy. It would be desirable to use an effective conventional immunosuppressive regimen in low doses or for a short course as an adjunct; however, cyclosporine treatment drastically blunts the ability of costimulation blockade to produce long-term engraftment. METHODS: Short courses of cyclosporine or rapamycin were compared as adjuncts to costimulation blockade in the murine BALB/c to C3H/He heterotopic cardiac allograft model. RESULTS: Although cyclosporine therapy blocked the capacity of costimulation blockade to produce permanent engraftment, combined rapamycin and costimulation blockade treatment produced permanent engraftment. CONCLUSION: A theoretical basis for the differing effects of cyclosporine and rapamycin upon the outcome of costimulation blockade is forwarded. Combined use of costimulation blockade and rapamycin may provide a means to bring costimulation blockade into the clinic.

Abatacept↗
PubMed1998

Cytotoxic lymphocyte gene expression in peripheral blood leukocytes correlates with rejecting renal allografts.

BACKGROUND: We have shown previously that heightened expression of the cytotoxic lymphocyte (CL) effector genes perforin (P), granzyme B (GB), and Fas ligand (FasL), is closely correlated with acute allograft rejection, particularly when two or more target genes are up-regulated. METHODS: We used quantitative reverse transcription-polymerase chain reaction to analyze CL gene expression from peripheral blood leukocytes (PBLs) and renal allograft biopsies in 31 paired samples of PBLs and renal tissue from 25 renal allograft recipients. Our aims were (1) to determine whether the expression of CL gene expression in PBLs correlates with expression of these genes in renal allograft biopsy tissue and (2) to determine whether CL gene expression in PBLs correlates with the histological diagnosis. RESULTS: Coordinate gene expression in PBLs and acutely rejecting allografts was found in 9/11 (82%) for P, 07/11 (64%) for GB, and 10/11 (91%) for FasL. Coordinate absence was found in 15/20 (75%) for P, 17/20 (85%) for GB, and 16/20 (80%) for FasL in nonrejecting allografts. Furthermore, up-regulation of any two genes in PBLs correlated with pathological diagnosis of rejection with excellent positive (100%) and negative (95%) predictive values. CONCLUSION: Coordinate CL gene expression in PBLs and the allograft is usually detected. CL gene expression in PBLs is closely associated with a pathologic diagnosis of rejection. CL gene expression in PBLs may serve as a noninvasive method of monitoring for renal allograft rejection.

Adult↗
PubMed1998

On histocompatibility barriers, Th1 to Th2 immune deviation, and the nature of the allograft responses.

In the present study, we have sought to determine the basis for the frequent failure of Th1 to Th2 immune deviation to blunt the severity of allograft rejection, as such immune deviation has proven highly effective in the treatment of several T cell-dependent autoimmune states. Our study demonstrates that treating islet allograft recipient mice with anti-IL-12 mAb is highly effective in producing Th1 to Th2 immune deviation in several model systems (i.e., fully MHC, partially MHC, or multiple minor Ag barriers). Nevertheless, anti-IL-12 failed to prolong the engraftment of fully MHC-mismatched islet allografts. However, anti-IL-12-treated recipients carrying MHC-matched but multiple minor Ag-mismatched allografts experienced prolonged engraftment; allograft tolerance was frequently achieved in the DBA/2J (H-2d) to BALB/c (H-2d) strain combination. In another model, in which the host response was dominated by CD4+ T cells responding to donor allopeptides presented upon host APCs in the context of self MHC class II molecules, anti-IL-12 treatment proved to be extremely potent. Thus, Th1 to Th2 immune deviation produces prolonged engraftment as compared with recipients of MHC-mismatched allografts when rejection is dependent upon indirectly presented allogeneic peptides and a reduced mass of responding alloreactive T cells.

Animals↗
PubMed1998

Augmentation and suppression of immune responses to an HIV-1 DNA vaccine by plasmid cytokine/Ig administration.

The use of cytokines has shown promise as an approach for amplifying vaccine-elicited immune responses, but the application of these immunomodulatory molecules in this setting has not been systematically explored. In this report we investigate the use of protein- and plasmid-based cytokines to augment immune responses elicited by an HIV-1 gp120 plasmid DNA vaccine (pV1J-gp120) in mice. We demonstrate that immune responses elicited by pV1J-gp120 can be either augmented or suppressed by administration of plasmid cytokines. A dicistronic plasmid expressing both gp120 and IL-2 induced a surprisingly weaker gp120-specific immune response than did the monocistronic pV1J-gp120 plasmid. In contrast, systemic delivery of soluble IL-2/Ig fusion protein following pV1J-gp120 vaccination significantly amplified the gp120-specific immune response as measured by Ab, proliferative, and CTL levels. Administration of plasmid IL-2/Ig had different effects on the DNA vaccine-elicited immune response that depended on the temporal relationship between Ag and cytokine delivery. Injection of plasmid IL-2/Ig either before or coincident with pV1J-gp120 suppressed the gp120-specific immune response, whereas injection of plasmid IL-2/Ig after pV1J-gp120 amplified this immune response. To maximize immune responses elicited by a DNA vaccine, therefore, it appears that the immune system should first be primed with a specific Ag and then amplified with cytokines. The data also show that IL-2/Ig is more effective than native IL-2 as a DNA vaccine adjuvant.

AIDS Vaccines↗
PubMed1998

Differential expression of T-cell growth factors in rejecting murine islet and human renal allografts: conspicuous absence of interleukin (IL)-9 despite expression of IL-2, IL-4, IL-7, and IL-15.

BACKGROUND: Interleukin (IL)-2, IL-4, IL-7, IL-9, and IL-15, all T-cell growth factors (TCGFs), utilize the common IL-2 receptor gammac chain as a critical signaling component in their receptor complexes. We have bred IL-2-/- and IL-4-/- double knockout (DKO) mice and showed vigorous islet allograft rejection by DKO hosts. The identity of TCGFs that support the IL-2- and IL-4-independent allograft rejection is unclear. METHODS: We analyzed IL-9 gene expression in rejecting islet allografts in wild-type and in DKO mice, as well as in human renal transplant biopsy specimens, by reverse transcriptase polymerase chain reaction and compared the expression of IL-9 with that of other TCGFs. RESULTS: IL-9 gene expression was not detected in rejecting murine islet allografts in either wild-type or DKO recipient mice despite robust expression of other TCGFs, including IL-7 and IL-15. IL-9 transcripts were also not expressed in any of the human renal transplant biopsies obtained 4 to 251 days after transplantation, regardless of the presence or absence of histological evidence of rejection. Despite expression of IL-9 by DKO splenic cells upon in vitro mitogenic stimulation, IL-9 alone was unable to stimulate the proliferation of concanavalin A-activated splenic leukocytes harvested from DKO mice. CONCLUSION: IL-9 is conspicuously absent despite vigorous expression of IL-2, IL-4, IL-7, and IL-15 genes during acute allograft rejection.

Animals↗