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Biomedical subjects

M Suthanthiran

Publications and source records attributed to M Suthanthiran.

At least 37 records · Page 2Linked to original sources
PubMed1998

Transforming growth factor-beta 1 hyperexpression in African American end-stage renal disease patients.

End-stage renal disease (ESRD) is more frequent in African Americans (blacks) compared to Caucasian Americans (whites). Identification of remediable causes of the increased prevalence has the potential to reduce the excess burden of ESRD. Because renal fibrosis is a correlate of progressive renal failure and a dominant feature of ESRD, and because transforming growth factor-beta 1 (TGF-beta 1) can induce fibrosis and renal insufficiency, we explored the hypothesis that TGF-beta 1 hyperexpression is more frequent in black ESRD patients compared to white ESRD patients. Our postulate was tested by determining circulating levels of TGF-beta 1 protein in the sera of 56 black and 42 white ESRD patients treated by chronic hemodialysis. A solid-phase sandwich enzyme-linked immunosorbent assay, specific for TGF-beta 1, was used to quantify TGF-beta 1 levels in the ESRD cohort. Additional cytokines implicated in tissue repair/remodeling, interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha), were also measured. Our investigation demonstrated a significantly higher concentration of TGF-beta 1 protein but not that of IL-6 or TNF-alpha in blacks compared to whites. Our observation that TGF-beta 1 is hyperexpressed in black ESRD patients suggests a mechanism for the increased prevalence of renal failure (since TGF-beta 1 hyperexpression can result in renal insufficiency in experimental models) among the black population.

Black People↗
PubMed1997

In vivo hyperexpression of transforming growth factor-beta1 in mice: stimulation by cyclosporine.

BACKGROUND: We have demonstrated that cyclosporine (CsA) stimulates transforming growth factor (TGF) beta1 expression in vitro and that growth of mammalian cells can be arrested by CsA via a TGF-beta1-dependent mechanism. Herein, we have explored whether CsA stimulates TGF-beta1 hyperexpression in vivo. METHODS: Four groups of B6AF1 mice were studied: group 1, control; group 2, CsA pretreatment; group 3, anti-CD3 monoclonal antibody pretreatment; and group 4, CsA plus anti-CD3 pretreatment. RESULTS: CsA pretreatment augmented TGF-beta1 protein expression and increased intrarenal display of TGF-beta1 mRNA. This heightened TGF-beta1 expression was associated with an impaired T cell proliferative response. CONCLUSIONS: Our observations, together, advance the hypothesis that CsA might function in vivo as an immunosuppressant not only by inhibiting the expression of proinflammatory cytokines (e.g., interleukin 2), but also by stimulating the expression of TGF-beta1, a potent immunosuppressive cytokine. Moreover, prevention of TGF-beta1 hyperexpression might prevent CsA-associated renal fibrosis, as TGF-beta1 is a fibrogenic cytokine.

Animals↗
PubMed1997

Intracellular Ca2+ elevation and cyclosporin A synergistically induce TGF-beta 1-mediated apoptosis in lymphocytes.

Apoptosis plays an essential role in the development and homeostasis of the immune system. During lymphocyte development, potentially autoreactive cells are eliminated via the activation of a tightly regulated cell death program(s). Similar processes operate in mature lymphocytes, to control the magnitude of the normal immune response by eliminating activated lymphocytes. However, differences in susceptibility to signal-induced apoptosis between immature and mature lymphocytes are numerous. One well-characterized example occurs in response to Ca2+ elevation: peripheral T lymphocytes are resistant, while immature thymocytes are highly susceptible, to Ca2+-mediated cell death (CMCD). In this study, we show that the immunosuppressant cyclosporin A (CsA) primes splenic lymphocytes to undergo CMCD upon ionomycin stimulation. This CsA-induced CMCD affected both T and B lymphocytes. CsA-plug Ca2+-mediated apoptosis was dissected into a two-step process: first, CsA and Ca2+ synergized to induce TGF-beta 1 secretion by B cells; and then TGF-beta 1 and Ca2+ synergistically triggered T and B lymphocyte apoptosis. Together, our results suggest that lymphocyte apoptosis may play a role in CsA-induced immunosuppression via a TGF-beta-dependent mechanism.

Animals↗
PubMed1997

Immunoregulatory drugs: mechanistic basis for use in organ transplantation.

Multiple immunoregulatory drugs, capable of constraining cell activation, differentiation, and/or proliferation, and each with distinct side effects, are currently used in the clinic to facilitate organ engraftment. Cyclosporine, azathioprine, corticosteroids, FK506 (tacrolimus), and RS61443 (mycophenolate mofetil) have already been approved by the United States Food and Drug Administration. Rapamycin (sirolimus), mizoribine, and 15-deoxyspergualin are being explored for their clinical efficacy. Based on their subcellular site of action, the immunosuppressants can be considered as: inhibitors of transcription (cyclosporine, tacrolimus), inhibitors of nucleotide synthesis (azathioprine, mycophenolate mofetil, mizoribine), inhibitors of growth factor signal transduction (sirolimus), and inhibitors of differentiation (15-deoxyspergualin). Clearly, the transplant clinician now has a greater choice in the selection and application of immunosuppressants in the clinic for the fine regulation of anti-allograft immunity. The existing hypothesis regarding the mechanisms of action of immunosuppressants is that they all function to prevent allograft rejection by preventing/inhibiting cell activation, cytokine production, differentiation, and/or proliferation. A complementary supposition is that some of the immunosuppressants might regulate the anti-allograft repertory by stimulating the expression of immunosuppressive molecules and/or cells.

Animals↗
PubMed1997

Immunostimulatory therapy with anti-CD3 monoclonal antibodies and recombinant interleukin-2: heightened in vivo expression of mRNA encoding cytotoxic attack molecules and immunoregulatory cytokines and regression of murine renal cell carcinoma.

The response rate to IL-2 immunotherapy, currently used in the treatment of metastatic renal cell cancer, is limited. Based on our earlier demonstration that a combined regimen of monoclonal antibodies directed at the T cell surface protein CD3 (anti-CD3 mAbs) and IL-2 is synergistic in constraining tumor progression in a murine fibrosarcoma hepatic metastasis model, we have explored the efficacy of an anti-CD3 mAbs plus IL-2 regimen in a murine renal cell cancer model. Our studies demonstrate that a regimen of anti-CD3 mAbs plus IL-2 is superior to treatment with anti-CD3 mAbs alone or IL-2 alone in reducing the number of pulmonary metastases and in prolonging survival. Moreover, the efficacious regimen is associated with heightened intrapulmonary expression of mRNA encoding cytotoxic attack molecules (perforin, granzyme B) and immunoregulatory cytokines (IL-4, IL-10 and IFN- gamma).

Animals↗
PubMed1997

Clinical application of molecular biology: a study of allograft rejection with polymerase chain reaction.

This article explores the clinical usefulness of reverse transcriptase-polymerase chain reaction in organ graft recipients. In this study, reverse transcriptase-polymerase chain reaction was used to identify intrarenal expression of cytotoxic attack molecules (granzyme B and perforin) and immunoregulatory cytokines (IL-2, IL-4, IL-10, IFN-gamma, and TGF-beta 1) in human renal allograft biopsies. The biopsies (n = 127) were classified using the Banff criteria, and intrarenal gene expression was correlated with the histologic diagnosis. Molecular analyses revealed that intragraft display of mRNA encoding granzyme B, IL-10, or IL-2 is a correlate of acute rejection, and intrarenal expression of TGF beta 1 mRNA is a correlate of chronic rejection. In addition to demonstrating differential and highly selective intragraft gene expression during rejection, these data suggest that therapeutic strategies directed at the molecular correlates of rejection might refine existing antirejection strategies.

Cytokines↗
PubMed1997

Effect of nifedipine on renal allograft function and survival beyond one year.

We previously reported that a calcium channel blocker supplemented immunosuppression produced excellent patient and graft survival rates in cadaveric kidney transplantation. We report here the long term outcome of patients treated with nifedipine-supplemented triple immunosuppression as compared with those of historical controls who were treated similarly without nifedipine. Study subjects included 111 patients transplanted in 1990-1994, treated with nifedipine and triple immunosuppression and with functioning grafts for more than one year (Nifedipine group). The results of cyclosporine (CyA) dose, blood pressure (BP), serum creatinine (Cr), and actuarial graft survival rate (GSR) up to 5 years posttransplant in these patients were compared with those of 52 patients transplanted in 1985-1990, treated similarly without calcium channel blockers (Control group). Donor sources, gender ratio, age distribution, causes of end stage renal disease, incidence of hypertension prior to transplantation and incidence of rejection in the first year between the groups were comparable. Throughout the study period the Nifedipine group had significantly lower serum Cr (1.5 +/- 0.7 vs. 1.8 +/- 0.7 mg/dl) and higher GSR (93.8% vs. 88% at 5 years) than the Control group. BP was comparable despite higher CyA doses in the Nifedipine group (4.3 +/- 1.1 vs. 3.3 +/- 1.1 mg/kg/day). We conclude that nifedipine is beneficial in improving long-term graft function and survival in kidney transplant recipients by mitigating CyA associated renal injury.

Adult↗
PubMed1997

Molecular analyses of human renal allografts: differential intragraft gene expression during rejection.

Reverse transcriptase-polymerase chain reaction (RT-PCR) was used to identify intrarenal expression of cytotoxic attack molecules (granzyme B and perforin) and immunoregulatory cytokines (IL-2, IL-4, IL-10, IFN-gamma, and TGF-beta 1) in 127 human renal allograft biopsies. The biopsies were classified using the Banff criteria, and intrarenal gene expression was correlated with the histological diagnosis. Molecular analyses revealed that intragraft display of mRNA encoding granzyme B, IL-10 or IL-2 is a correlate of acute rejection, and intrarenal expression of TGF beta 1 mRNA, of chronic rejection. These data, in addition to demonstrating differential and highly selective intragraft gene expression during rejection, suggest that therapeutic strategies directed at the molecular correlates of rejection might refine existing anti-rejection strategies.

Biopsy↗
PubMed1996

Molecular executors of cell death--differential intrarenal expression of Fas ligand, Fas, granzyme B, and perforin during acute and/or chronic rejection of human renal allografts.

Two distinct cytolytic pathways have been characterized: one in which the interaction between the Fas antigen and its ligand results in apoptosis, and another in which the pore forming protein perforin and the serine protease granzyme B contribute to DNA fragmentation and cell death. We investigated intrarenal expression of these molecular executors of cell death in light of the potential participation of cytolytically active cellular elements in the antiallograft repertory. Reverse transcriptase-polymerase chain reaction was used to identify intrarenal expression of Fas antigen, Fas ligand, granzyme B and perforin in eighty human renal allograft biopsies; mRNA display was correlated with the Banff histological diagnosis of renal allografts. Our studies demonstrate that: (1) intrarenal expression of Fas ligand mRNA and of granzyme B mRNA are correlates of acute but not chronic rejection; (2) Fas ligand mRNA is not detectable in allografts in the absence of rejection; (3) intrarenal coexpression of members of each lytic pathway (Fas ligand and Fas, granzyme B, and perforin) and that of both pathways (e.g., Fas ligand and granzyme B) are correlates of acute rejection; and (4) a direct correlation exists between the histological severity of acute rejection and intrarenal coexpression of mRNA encoding Fas ligand, Fas, granzyme B, and perforin. Our studies identify, for the first time, the differential expression of the two major lytic pathways in acute and chronic allograft rejection and suggest that specific therapy directed at the cytotoxic attack molecules might be efficacious in the prevention and/or treatment of acute rejection.

Acute Disease↗
PubMed1996

CD2 antigen targeting reduces intragraft expression of mRNA-encoding granzyme B and IL-10 and induces tolerance.

We explored the hypothesis that CD2 antigen-specific therapy would reduce intragraft gene expression and facilitate the emergence of transplantation tolerance. This postulate was tested in a murine pancreatic islet cell allograft model in which a novel mAb directed at the CD2 antigen, RM2-2 anti-CD2 mAb (RM2-2 mAb), was used to regulate CD2 antigen-dependent antiallograft response. Peritransplant administration (day -1, 0, and day + 1 with respect to transplantation) of RM2-2 mAb resulted in significantly longer survival of DBA/2 pancreatic islet cell allografts in the B6AFl recipient compared with untreated recipients. RM2-2 mAb therapy facilitated the induction of antigen-specific tolerance: whereas retransplantation with the original donor strain (DBA/2) islet cell allograft was successful, retransplantation with a third-party donor (SJL) islet cell allograft was not. In vivo administration of RM2-2 mAb therapy resulted in a decrease in the percentage of T cells that coexpressed the CD2 antigen (demonstrated by two-color flow cytometry) and in a decrease in intragraft expression of cytotoxic cell specific granzyme B mRNA and IL-10 mRNA (detected by RT-PCR). Our data, in addition to demonstrating for the first time the efficacy of RM2-2 anti-CD2 mAb, suggest that CD2 antigen is a suitable target for the induction of transplantation tolerance.

Animals↗
PubMed1996

Immunosuppressants: cellular and molecular mechanisms of action.

The basic immunosuppressive protocol used in most transplant centers involves the use of multiple drugs, each directed at a discrete site in the T-cell activation cascade and each with distinct side effects. Cyclosporine, azathioprine, corticosteroids, FK506 (tacrolimus), and RS61443 (mycophenolate mofetil) have been approved by the Food and Drug Administration, and the clinical efficacy of rapamycin (sirolimus), mizoribine, 15-deoxyspergualin, and leflunomide is being explored. Based on their primary site of action, the immunosuppressants can be classified as inhibitors of transcription (cyclosporine, tacrolimus), inhibitors of nucleotide synthesis (azathioprine, mycophenolate mofetil, mizoribine, leflunomide), inhibitors of growth factor signal transduction (sirolimus, leflunomide), and inhibitors of differentiation (15-deoxyspergualin). Polyclonal antilymphocyte antibodies, monoclonal antibodies directed at the T-cell antigen receptor complex (OKT3, TIOB9), and monoclonal antibodies directed at additional cell surface antigens, including interleukin-2 receptor alpha, afford cell-specific regulation of the immune response and are being used in the clinical setting as induction therapy and/or antirejection drugs. Clearly, the transplant clinician now has a greater choice in the selection and application of immunosuppressants in the clinic for the fine regulation of the antiallograft repertory. The prevailing paradigm regarding the mechanisms of action of immunosuppressants is that they all function to prevent allograft rejection by preventing/inhibiting cell activation, cytokine production, differentiation, and/or proliferation. One hypothesis, albeit provocative, is that some of the immunosuppressants might function by stimulating the expression of immunosuppressive molecules and/or cells.

Humans↗
PubMed1996

Intragraft TGF-beta 1 mRNA: a correlate of interstitial fibrosis and chronic allograft nephropathy.

Chronic allograft nephropathy is a relentlessly progressive process and a major cause of long-term graft dysfunction and ultimate failure. Interstitial fibrosis, tubular atrophy, and glomerular and vascular lesions characterize this mechanistically unresolved disorder. Given the prominent role of TGF-beta 1 in tissue repair and in fibrosis, we have explored the hypothesis that fibrosis and chronic allograft nephropathy would be distinguished by intragraft TGF-beta 1 mRNA expression. This postulate was tested by mRNA phenotyping of RNA isolated from 127 human renal allograft biopsies. Reverse transcription assisted polymerase chain reaction was used to amplify and identify ingraft gene expression. Our investigation demonstrated a significant correlation between intragraft TGF-beta 1 mRNA display and renal allograft interstitial fibrosis and chronic allograft nephropathy. In contrast, intragraft expression of mRNA encoding immunoregulatory cytokines, IL-2, IFN-gamma, IL-4, IL-10, or cytotoxic attack molecules, granzyme B and perforin was not a correlate of interstitial fibrosis or chronic allograft nephropathy. Our studies identify, for the first time, a significant association between intragraft TGF-beta 1 mRNA expression and renal allograft interstitial fibrosis, and advance a candidate molecular mechanism for chronic allograft nephropathy.

Base Sequence↗
PubMed1996

Regulation of the anti-allograft response by targeting the CD2 antigen: a potential strategy for the creation of transplant tolerance.

Activated T cells playa central role in the rejection of histoincompatible organ allografts. Studies of trans- membrane signaling requirements ofT cells, by identifying molecular and cellular mechanisms ofT-cell activation, can lead to rational therapeutic strategies for the regulation of the anti-allograft response. A clear consensus exists that the primary signal for T-cell activation is generated as a consequence of the in- teractions among the T-cell receptor for antigen (TCR)I cluster designation 3 (CD3) complex and the antigenic peptide presented in the context of major histocompatibility complex (MHC) proteins expressed on the sur- face of the antigen-presenting cells (APCs). '-7 The TCR/CD3-dependent signaling is necessary but insufficient in itself to fully activate normal human primary (quiescent) T cells, and additional costimulatory signals are required for full activatiori.

Journal Article↗