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Biomedical subjects

M Suthanthiran

Publications and source records attributed to M Suthanthiran.

At least 55 records · Page 3Linked to original sources
PubMed1996

Transforming growth factor-beta 1: regulation with a TGF-beta 1 antisense oligomer.

Transforming growth factor-beta 1 (TGF-beta 1) is a member of a family of polypeptides important in embroygenesis, tissue repair and cell growth. On the other hand, TGF-beta 1 is considered to be a causative factor in organ dysfunction and in immune deregulation of AIDS. The proteoglycan decorin and anti-TGF-beta antibodies have been used to mitigate the adverse consequences of TGF-beta 1 overexpression. We describe here a novel TGF-beta 1 complementary DNA (antisense oligomer) that is specific for TGF-beta 1 genomic DNA. The TGF-beta 1 antisense oligomer, complementary to the nucleotides flanking the first transcription start site of the human TGF-beta 1 gene and phosphorothioate modified, was efficacious in: (a) constraining TGF-beta 1 promoter activity; (b) reducing TGF-beta 1 secretion; (c) preventing TGF-beta 1 dependent inhibition of DNA synthesis; and (d) inhibiting phenotypic alterations in TGF-beta sensitive A-549 human adenocarcinoma cells. Our findings, in addition to demonstrating the efficacy of the TGF-beta 1 antisense oligomer, suggest that the oligomer might be of value for the treatment of diseases in which TGF-beta 1 overexpression might play a pathogenetic role.

Adenocarcinoma↗
PubMed1995

Retrievable, replaceable, macroencapsulated pancreatic islet xenografts. Long-term engraftment without immunosuppression.

Prevention of rejection and prolongation of graft survival are critical to achieving successful islet cell transplantation. Various techniques have been utilized to prolong graft survival. Recently, protection of pancreatic islets from host immune mechanisms by isolating the islets in artificial membranes has emerged as an attractive alternative to the use of immunosuppression. In this Rapid Communication, we describe a novel method for macroencapsulation of rat islets in hydrophilic macrobeads made with various combinations of agarose, collagen, and Gelfoam. Encapsulated xenotypic islets were placed intraperitoneally in mice in which diabetes was induced by streptozotocin. The encapsulated xenografts maintained normoglycemia > 170 days. Recipients mice had normal glucose tolerance tests, which indicates that the islets in the macrobeads were functioning as they would in an intact pancreas. Macrobeads retrieved up to 103 days after transplantation showed no evidence of tissue reaction or local inflammation. These retrieved macrobeads could also be retransplanted and replaced. Our studies indicate that the agarose-collagen/Gelfoam macrobeads we have developed serve both to protect islet xenografts from rejection and to provide a microenvironment in which the islets maintain and support their normal function in vivo. Because they may be retrieved after implantation and replaced, these macrobeads may be suitable for human clinical islet cell xenotransplantation.

Animals↗
PubMed1995

Stimulation of transforming growth factor-beta 1 transcription by cyclosporine.

In searching for a candidate mechanism for the immunosuppressive as well as fibrogenic consequences of cyclosporine usage, we have explored the hypothesis that cyclosporine stimulates transcription of transforming growth factor-beta 1 (TGF-beta 1), a multifunctional cytokine endowed with immunosuppressive and fibrogenic properties. Our results demonstrate that cyclosporine (i) stimulates TGF-beta 1 promoter-dependent transcription of chloramphenicol acetyl transferase gene in transiently transfected human A-549 cells, (ii) stimulates the synthesis of TGF-beta 1 RNA transcripts in human T cells, and (iii) permits the expression/emergence of DNA regulatory proteins (retinoblastoma control factor-1 (RCF-1) and RCF-2) that bind and regulate TGF-beta 1 promoter activity. Our studies demonstrate for the first time that cyclosporine stimulates TGF-beta 1 gene transcription and suggest a novel mechanism of action of cyclosporine.

Base Sequence↗
PubMed1995

Immunobiology and immunopharmacology of organ allograft rejection.

Much has been learned regarding immunobiological mechanisms responsible for the rejection of histoincompatible allografts. There has also been considerable progress in our understanding of mechanisms responsible for tolerance. The new knowledge gained regarding graft destructive alloimmunity process and the mechanisms of action of immunosuppressants have resulted in solid organ graft survival rates that are in excess of 80% at one year posttransplantation. The principles of tolerance mechanism are yet to be successfully applied in the clinic. In this review, molecular and cellular mechanisms of action of clinically useful immunosuppressive drugs are reviewed from the perspective of regulation of the anti-allograft repertory.

Graft Rejection↗
PubMed1994

Regulation of transforming growth factor-beta 1 (TGF-beta 1) expression with a novel TGF-beta 1 complementary DNA.

We describe here a novel TGF-beta 1 complementary DNA (antisense oligomer) that is specific for TGF-beta 1 genomic DNA. The TGF-beta 1 antisense oligomer, complementary to the nucleotides flanking the first transcription start site of the human TGF-beta 1 gene and phosphorothioate modified, was efficacious in: a) constraining TGF-beta 1 promoter activity; b) reducing TGF-beta 1 secretion; and c) preventing TGF-beta 1 dependent inhibition of DNA synthesis in TGF-beta sensitive A-549 human adenocarcinoma cells. The biologic activities of the TGF-beta 1 antisense oligomer were sequence specific since neither the TGF-beta 1 sense oligomer nor the TGF-beta 1 missense oligomer prevented TGF-beta 1 expression. Our findings, in addition to demonstrating the efficacy and specificity of the TGF-beta 1 antisense oligomer, suggest that the oligomer might be of value for the treatment of diseases in which TGF-beta 1 overexpression might play a pathogenetic role (e.g., diabetic renal disease, AIDS).

Adenocarcinoma↗
PubMed1994

Immunotherapy with anti-CD3 monoclonal antibodies and recombinant interleukin 2: stimulation of molecular programs of cytotoxic killer cells and induction of tumor regression.

Adoptive cellular immunotherapy, infusions of interleukin 2 (IL-2) in conjunction with in vitro-activated killer cells, has brought new hope to patients with cancer. The broad application of this strategy, however, is constrained by the need for repeated leukapheresis and by the labor-intensive process of in vitro activation of cells. Also, current protocols generally use nonphysiological and toxic concentrations of IL-2. Identification of an in vivo stimulant that renders T cells responsive to physiologic concentrations of IL-2 represents a potential improvement over existing approaches. We have determined whether in vivo administration of monoclonal antibodies (mAbs) directed at the T-cell surface protein CD3 induces T-cell responsiveness to IL-2, stimulates cytolytic molecular programs of natural killer cells and cytotoxic T cells, and induces tumor regression. These hypotheses were explored in a murine hepatic MCA-102 fibrosarcoma model. We report that in vivo administration of anti-CD3 mAbs plus IL-2 results in intrahepatic expression of mRNA-encoding perforin, cytotoxic T-cell-specific serine esterase, and tumor necrosis factor alpha. Anti-CD3 mAbs alone or IL-2 alone failed to induce or induced minimal expression of these molecular mediators of cytotoxicity. The anti-CD3 mAbs plus IL-2 regimen also resulted in a significantly smaller number of hepatic metastases and a significantly longer survival time of tumor-bearing mice, compared to treatment with anti-CD3 mAbs alone or IL-2 alone. Our findings suggest that a regimen of anti-CD3 mAbs plus IL-2 is a more effective antitumor regimen compared with anti-CD3 mAbs alone or IL-2 alone and advance an alternative immunotherapy strategy of potential value for the treatment of cancer in humans.

Animals↗
PubMed1994

Regulation of new DNA synthesis in mammalian cells by cyclosporine. Demonstration of a transforming growth factor beta-dependent mechanism of inhibition of cell growth.

Immunosuppressants such as cyclosporine are considered to constrain cell growth by preventing the production of growth stimulatory cytokines (e.g., interleukin-2). The possibility exists, however, that CsA and other immunosuppressants might restrain cell growth by promoting the production of growth-inhibitory cytokines. We have explored herein the hypothesis that CsA stimulates the production of transforming growth factor-beta (TGF-beta), and restrains new DNA synthesis in mammalian cells via a TGF-beta-dependent mechanism. To investigate this new postulate independently of an IL-2-dependent mechanism, we utilized, as probes, two mammalian cell lines, distinguished by their sensitivity to growth inhibition by TGF-beta and resistance to IL-2: CCL-64 mink lung epithelial cells (CCL-64 cells) and A-549 human adenocarcinoma cells (A-549 cells). Our experimental approach revealed the following: (A) CsA and not cyclosporine H, an inactive analogue of CsA, mediates growth inhibition of TGF-beta-sensitive cells, CCL-64 cells, and A-549 cells; (B) CsA stimulates these mammalian cells to secrete TGF-beta; and (C) TGF-beta induced by CsA is biologically active in inducing cell growth inhibition (demonstrated by the reversal of CsA-associated inhibition with anti-TGF-beta monoclonal antibodies). Our observations suggest that CsA can regulate cell growth via a TGF-beta-dependent mechanism. Since the multifunctional cytokine TGF-beta can enhance extracellular matrix accumulation as well as augment endothelin production, our findings also advance a mechanism that links, via TGF-beta, the beneficial (immunosuppression) and the harmful (fibrosis, hypertension) consequences of CsA usage.

Animals↗
PubMed1994

Which way for drug-mediated immunosuppression?

The basic immunosuppressive protocol involves the use of multiple drugs, each directed at a discrete site in the T-cell activation cascade. The prevailing paradigm regarding the mechanisms of action of immunosuppressants is that they function to prevent allograft rejection by preventing cell activation, proliferation and/or cytokine production. A new hypothesis is that some of the immunosuppressants might function by stimulating the expression of immunosuppressive molecules and/or cells.

Animals↗
PubMed1994

Modulation of mouse mesangial cell proliferation by thiourea and lipoxygenase inhibitors.

This paper investigates factors involved in mesangial cell (MC) proliferation by focussing on the proliferative effects of phorbol myristate acetate (PMA) on mouse MC in culture in comparison to those of fetal calf serum (FCS). The potential roles of cyclooxygenase and lipoxygenase products of arachidonic acid metabolism and of hydroxyl radicals on their proliferation are addressed. The results indicate: (1) that PMA can induce proliferation of MC; (2) that inhibition of prostaglandin synthesis by indomethacin does not modify PMA-induced proliferation but enhances the proliferative response to FCS, and (3) that stimulation of MC proliferation by PMA or FCS is inhibited by agents interfering with the generation of products of the lipoxygenase pathway and hydroxyl radical scavengers. The role of lipoxygenase products and reactive oxygen species in MC proliferation deserves further investigation.

Animals↗
PubMed1993

Advanced glycosylation endproduct-specific receptors on human and rat T-lymphocytes mediate synthesis of interferon gamma: role in tissue remodeling.

During normal aging and in chronic diabetes the excessive accumulation of reactive glucose-protein or glucose-lipid adducts known as advanced glycosylation endproducts (AGEs) has been shown to induce tissue dysfunction, in part through interaction with AGE-specific receptors on monocyte/macrophages and other cells. Recognizing that circulating lymphocytes trafficking through tissues interact with tissue AGEs, we searched for the expression of AGE-binding sites on peripheral blood T lymphocytes. Resting rat and human T cells bound 125I-AGE-albumin with an affinity of 7.8 x 10(7) M-1, whereas, after stimulation with phytohemagglutinin (PHA) for 48 h, binding affinity increased to 5.8 x 10(8) M-1. Flow cytometric analysis of resting rat T cells using polyclonal antibodies raised against rat liver AGE-binding proteins (p60 and p90) revealed the constitutive expression of both immunoreactivities. The number of resting CD4+ and CD8+ T cells positive for anti-p60 antibody binding (34.2 and 58.5%, respectively) increased to 92 and 90% of cells after 48-h stimulation with PHA. Exposure of PHA-activated T lymphocytes to AGE-albumin enhanced expression of interferon gamma (IFN-gamma) mRNA 10-fold and induced greater elaboration of the mature protein than did exposure to unmodified protein or PHA treatment alone. These data indicate that T cells contain an inducible system of surface receptors for AGE-modified proteins, and that receptor occupancy is linked to lymphokine production. This T cell AGE-receptor system might serve to target lymphocytes to AGE-rich tissues and involve them in the regulation of tissue homeostasis either by assisting in macrophage-dependent clearance of AGE-proteins, or by exerting direct antiproliferative action on mesenchymal cells. Under conditions of excessive AGE-protein and AGE lipid accumulation (e.g., aging and diabetes), enhanced production of AGE-induced IFN-gamma may accelerate immune responses that contribute to tissue injury.

Animals↗
PubMed1993

Excellent outcome with a calcium channel blocker-supplemented immunosuppressive regimen in cadaveric renal transplantation. A potential strategy to avoid antibody induction protocols.

Many transplant centers routinely utilize monoclonal antibody or polyclonal antibody based induction protocols in recipients of cadaver renal allografts. Given the potential complications associated with antibody-based immunosuppression regimens (e.g., CMV disease), we tested the hypothesis that a combination of a calcium antagonist and a triple drug protocol (cyclosporine + prednisone + azathioprine) would be an effective substitute for antibody-based induction protocols in ensuring excellent patient and graft survival rates. Our postulate was tested in a prospective study of 52 consecutive recipients of cadaver renal allografts (44 first, 5 second, and 3 third grafts) utilizing nifedipine as the first line calcium antagonist. Nifedipine was selected over verapamil or diltiazem due to its lack of interference with the metabolism of CsA. Some of the significant outcomes of our prospective trial were (A) a cumulative patient survival rate of 98.1% for the 52 recipients at 18 months posttransplantation; (B) a cumulative allograft survival rate of 92.1% for the 52 consecutive cadaver renal allografts at 18 months; (C) a cumulative allograft survival rate of 100% at 18 months for the 24 of 52 renal allografts without delayed graft function following transplantation; and (D) a cumulative allograft survival rate of 86% at 18 months for the 28 of 52 renal allografts with delayed graft function. Of the 4 of 52 who lost their grafts, 2 grafts were removed following discontinuation of immunosuppressive therapy while the remaining 2 had primary nonfunction; and (E) the lack of a requirement for monoclonal or polyclonal antibodies for the treatment of acute rejection episodes in this patient population. These gratifying results compare very favorably with (A) recent reports of the effects of long-term diltiazem therapy and of verapamil used in conjunction with an induction protocol that included Minnesota antilymphocyte globulin in recipients of cadaver renal allografts, and (B) the clinical outcome in many institutions with OKT3/ATG/ALG induction protocols. Whereas the mechanisms involved in the excellent clinical outcome found with the calcium antagonist remain undefined, our results strongly argue for a prospective, randomized and controlled study in which a calcium antagonist-supplemented immunosuppressive regimen is compared with antibody-based induction protocols.

Adult↗
PubMed1993

Synergism between the CD3 antigen- and CD2 antigen-derived signals. Exploration at the level of induction of DNA-binding proteins and characterization of the inhibitory activity of cyclosporine.

We have demonstrated earlier that the crosslinkage of the CD3/TCR complex with the CD2 antigen results in the proliferation of normal human T cells. The effect of this synergism was perceptible at the level of induction of the IL-2 gene, a process critical for T cell growth. To further understand the molecular and nuclear basis for this synergism, we have explored the induction of DNA-binding proteins in highly purified normal human T cells signaled via the CD3 and/or CD2 proteins. The effect of transmembrane signaling of T cells with ionomycin, and/or sn-1,2 dioctanoyl glycerol, was also determined. The emergence of nuclear binding proteins was investigated using interleukin-2 sequence specific oligonucleotide probes in the electrophoretic mobility shift assay. Our studies demonstrate for the first time that CD3 antigen-derived signals and CD2 antigen-derived signals are synergistic in inducing the emergence of transcription factors that bind to the NF-AT1, AP-1, and NF-kB sites located in the promoter/enhancer region of the IL-2 gene. Moreover, cyclosporine, at concentrations readily accomplished in clinical practice, was found to inhibit the emergence of these DNA-binding proteins in normal human T cells signaled via cell surface proteins implicated in antigen-dependent T cell activation and in T cells stimulated by mobilization of cellular calcium and activation of protein kinase C.

Antigens, Differentiation, T-Lymphocyte↗