Mechanism of action of the new immunomodulator LS2616 on T cell responses

Larsson, Eva‐Lotta; Joki, Annalena; Stålhandske, Torbjörn

doi:10.1016/0192-0561(87)90016-6

Cited by 74 publications

(28 citation statements)

References 20 publications

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“…Apoptosis also occurs following exposure of thymocytes to glucocorticoids (GC) such as dexamethasone, which lead to the rapid atrophy of the thymus [4]. Linomide, quinoline-3-carboxamide, (roquinimex, LS2616) has been shown to modulate a number of immune functions [5][6][7], foremost, Linomide has been shown to have a potent ameliorative effect in a variety of autoimmune disease models such as systemic lupus erythematosus (SLE)-like syndrome [8], experimental autoimmune encephalomyelitis [9] and insulin dependent diabetes mellitus [10]. In the SLE model, Linomide prolongs survival and delays organ pathology of MRL lpr/1pr mice.…”

Section: Introductionmentioning

confidence: 99%

Linomide Enhances Apoptosis in CD4⁺CD8⁺ Thymocytes

Harring

Andersson

et al. 1997

Scand J Immunol

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Harring A, Xu Z, Andersson G, Hedlund G. Linomide Enhances Apoptosis in CD4 þ CD8 þ Thymocytes. Scand J Immunol 1997;46:488-494 Linomide, a quinoline-3-carboxamide, has a pleiotropic immune modulating capacity and inhibits development as well as progression of disease in animal models of autoimmunity. Linomide treatment of mice resulted in a dramatic, dose-dependent decrease of the thymic cell number shortly after the start of administration. Flow cytometric analysis revealed that the major thymocyte subset, the early immature type CD4 þ CD8 þ thymocytes, were reduced in number by 75%, mature CD4 þ CD8 ¹ or CD4 ¹ CD8 þ thymocytes were less sensitive to treatment. The polyclonal T cell activator Con A (Concanavalin A) was used together with IL-2 to evaluate the potential proliferative responsiveness of ex vivo thymocytes. Thymocytes from mice treated with Linomide exhibited a more vigorous proliferation than control cultures. An effect shown to not only be due to the enrichment of mature thymocytes in the cultures from Linomide treated animals, but also when purified, mature thymocytes (CD4 þ CD8 ¹ and CD4 ¹ CD8 þ ) were cultured with Con A and IL-2, these cells responded with a significantly enhanced proliferation. In vivo Linomide treatment did not result in increased plasma concentrations of corticosterone and treatment of adrenalectomized mice resulted in a reduction of thymocytes which was comparable to the effect in intact mice, indicating that glucocorticoids (GC) are not major mediators of Linomide-induced thymocyte deletion. In addition to this, and supporting a glucocorticoid independent mode of action, Linomide treatment of thymocytes in vitro resulted in a significant increase in the number of apoptotic cells, specifically in the CD4 þ CD8 þ subset, implicating apopotosis as one component in the course of thymocyte reduction. In addition to this, in vivo treatment with Linomide resulted in an identical pattern to that seen in vitro in that there was significantly increased apoptosis only in the CD4 þ CD8 þ . These data indicate that Linomide modifies thymocyte development using a glucocorticoid independent pathway and results in the increased apoptosis of the CD4 þ CD8 þ subset.

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Section: Introductionmentioning

confidence: 99%

Linomide Enhances Apoptosis in CD4⁺CD8⁺ Thymocytes

Harring

Andersson

et al. 1997

Scand J Immunol

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“…Evidence f o r a of 20-45%. STEM CELLS 1993;11(~~ppl3): [34][35][36][37][38][39][40][41][42] graft-versus-leukemia (GVL) effect is based on the increased rate of relapse in syngeneic transplants [24]; allogeneic transplants without graft-versus-host disease (GVHD) [25], and in most reports of T cell depleted donor transplants 171. The initial interpretation of these data was that T lymphocytes mediate both GVHD and GVL, with the two processes being interdependent.…”

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confidence: 99%

Allografting in chronic myelogenous leukemia followed by immunotherapy

et al. 1993

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Abstract. Patients with chronic myelogenous leukemia (CML) can be cured with allogeneic bone marrow transplantation. Over the past decade, it has become clear that immunological mechanisms, in the form of graft-versusleukemia, constitute an integral part of this therapy. Because of limitations imposed by a lack of suitable donors, age, and toxicity, only a minority of patients can be offered allogeneic bone marrow transplantation (BMT).Recently, attempts have been made to employ autologous bone marrow transplantation (ABMT) for the therapy of CML using a vanety of pre-and post-transplantation manipulations. This report describes the rationale for an ongoing clinical trial using the immunomodulator roquinimex (Lmomide), following autologous bone marrow transplantation, in an attempt to stimulate the immunological responses thought to be critical for successful therapy in CML.

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“…Linomide Ò itself does not accelerate cardiac graft rejection (compared with no treatment), presumably because graft rejection is an immunological process already occurring at the maximum rate. In other experimental settings, Linomide Ò has been shown to enhance natural killer (NK) cell activity [14], delayed-type hypersensitivity and antibody production [15], and to stimulate polyclonal T-cell activation [16]. Linomide Ò may also aggravate experimental autoimmune disease [17,18] as well as graft-vs.-host disease after semisyngeneic small bowel transplantation [19,20].…”

Section: Introductionmentioning

confidence: 99%

Tolerance or Rejection: A Delicate Balance as Judged by Exposure of Heart‐Transplanted Rats to the Immunomodulator Linomide^®

Tufveson

Ekberg

1999

Scand J Immunol

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When applied in rodent transplant models most immunosuppressive drugs yield adequate graft protection for as long as the drug is given, and permanent graft survival is often induced. The immunomodulator, Linomide Ò , previously shown to stimulate T cells and prevent apoptosis, usually reduces or abolishes both tolerance induction and the graft-protective effect of the immunosuppressive drug. By chance, we observed that Linomide Ò alone exerted a modest but unequivocal graft-protective effect in the BN to WF strain combination. This ®nding was analysed by simple genetic mapping of rat strains. Untreated WF recipients kept BN grafts for a median of 8 days, whereas Linomide Ò treatment prolonged graft survival to 12.5 days (P 0.0001). In control groups (DA to LEW, BN to LEW, DA to WF and WF to BN), median graft survival was 5.5±7 days irrespective of whether Linomide Ò was given. However, the BN to F1 (LEW´WF) combination also manifested slightly longer graft survival in the presence of Linomide ) may either cause on its own longterm survival of allografts in one setting or rejection despite optimal immunosuppression in another setting.

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Mechanism of action of the new immunomodulator LS2616 on T cell responses

Cited by 74 publications

References 20 publications

Linomide Enhances Apoptosis in CD4⁺CD8⁺ Thymocytes

Linomide Enhances Apoptosis in CD4⁺CD8⁺ Thymocytes

Allografting in chronic myelogenous leukemia followed by immunotherapy

Tolerance or Rejection: A Delicate Balance as Judged by Exposure of Heart‐Transplanted Rats to the Immunomodulator Linomide^®

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Mechanism of action of the new immunomodulator LS2616 on T cell responses

Cited by 74 publications

References 20 publications

Linomide Enhances Apoptosis in CD4+CD8+ Thymocytes

Linomide Enhances Apoptosis in CD4+CD8+ Thymocytes

Allografting in chronic myelogenous leukemia followed by immunotherapy

Tolerance or Rejection: A Delicate Balance as Judged by Exposure of Heart‐Transplanted Rats to the Immunomodulator Linomide®

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Linomide Enhances Apoptosis in CD4⁺CD8⁺ Thymocytes

Linomide Enhances Apoptosis in CD4⁺CD8⁺ Thymocytes

Tolerance or Rejection: A Delicate Balance as Judged by Exposure of Heart‐Transplanted Rats to the Immunomodulator Linomide^®