roquinimex and Graft-vs-Host-Disease

Topics: Acute Disease; Bone Marrow Transplantation; Graft vs Host Disease; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Hydroxyquinolines; Immunotherapy; Interferons; Interleukin-2; Leukemia; Macrophages; T-Lymphocytes

Topics: Bone Marrow Transplantation; Combined Modality Therapy; Forecasting; Graft vs Host Disease; Humans; Hydroxyquinolines; Immunologic Factors; Immunotherapy, Adoptive; Interleukin-2; Killer Cells, Natural; Leukemia

Transferring parental splenocytes into unirradiated F1 mice induces a chronic graft-versus-host disease (GVHD), characterized by the production of Th2 cytokines and immunocomplex-mediated glomerulonephritis resembling systemic lupus erythematosus (SLE). The effects of H1521, a new derivative of 4-hydroxyquinoline-3-carboxamide, were investigated in chronic GVHD lupus model. H1521 was administered to chronic GVHD mice for 10 weeks. Nephritic symptoms were monitored and cytokine expression in the spleen was detected. To clarify the direct effect of H1521 on CD4(+) T cell, CD4(+) T cells were isolated and co-cultured with H1521 under neutral and Th1 or Th2 driving conditions in vitro. H1521 (32 mg/kg) reduced the incidence of proteinuria by 50% in chronic GVHD mice. Ameliorated lupus symptoms and improved renal histopathology damage were also observed. Administration of H1521 had little impact on Th1 cytokine IL-2 and IFN-gamma or Th2 cytokine IL-4 and IL-10 mRNA expression. In contrast, severely deficient IFN-gamma production by concanavalin A-stimulated spleen cells in chronic GVHD mice was completely restored by H1521. In accordance with this, decreased T-bet mRNA expression became normalized with H1521 (32 mg/kg) treatment. In addition, in vitro studies demonstrated that H1521 preferentially favored Th1 differentiation in CD4(+) T cell and promoted IFN-gamma secretion in Th1 differential CD4(+) T cell. However, IL-4 secretion in naive or Th2 differential CD4(+) T cell was unaffected by H1521. In conclusion, H1521 can induce Th1 cytokine profile in CD4(+) T cells and has possible therapeutic value in Th2-predominant immune diseases.

Topics: Adjuvants, Immunologic; Animals; Chronic Disease; Cytokines; Disease Models, Animal; Female; Graft vs Host Disease; Hydroxyquinolines; Lupus Erythematosus, Systemic; Mice; Mice, Inbred Strains; Th1 Cells; Th2 Cells

Roquinimex is an immunomodulator that can effectively inhibit the development of several autoimmune diseases in animal models, but the mechanism is still unknown. In this study, we investigated the effect of roquinimex on chronic graft-versus-host disease (GVHD) in mice, a well-established model for human systemic lupus erythematosus (SLE). Oral administration of roquinimex significantly suppressed the development of proteinuria and ameliorated nephritis symptoms in chronic GVHD mice. In addition, renal histopathology and immunohistochemistry studies revealed reduced glomerulonephritis and decreased IgG deposition in chronic GVHD mice treated with roquinimex. Chronic GVHD is characterized by a predominance of Th2 cytokines, and proinflammatory cytokines that also play an important role in the pathology of tissue damage. Therefore, we focused on the effect of roquinimex on cytokine production. Chronic GVHD mouse splenocytes exhibited severely reduced interferon (IFN)-gamma production in response to Concanavalin (Con A) stimulation and an overt Th2 skewness. Roquinimex treatment, however, induced IFN-gamma production and restored the Th1/Th2 cytokine balance, although only a minimal effect of roquinimex on interleukin (IL)-4 secretion was observed. The production of the proinflammatory cytokines TNF-alpha and IL-1 beta by peritoneal macrophages from lipopolysaccharide (LPS)-treated GVHD mice was significantly inhibited by roquinimex treatment. These data suggested that the beneficial effect of roquinimex on lupus might, at least in part, result from a restoration of Th1/Th2 cytokine balance and inhibition of inflammatory cytokine production.

Topics: Adjuvants, Immunologic; Animals; Antibodies, Antinuclear; Blood Urea Nitrogen; Cells, Cultured; Cholesterol; Chronic Disease; Creatinine; Cytokines; Enzyme-Linked Immunosorbent Assay; Female; Graft vs Host Disease; Hydroxyquinolines; Immunoglobulin G; Inflammation Mediators; Kidney; Macrophages; Male; Mice; Mice, Inbred DBA; Proteinuria; Spleen; Th1 Cells; Th2 Cells; Triglycerides

A series of linomide-related quinoline-3-carboxamides and their analogues was prepared and evaluated for antinephritic activities. The 6-MeS derivative 7a was highly effective in two nephritis models, namely chronic graft-versus-host disease and autoimmune MRL/l mice.

Topics: Amides; Animals; Antibodies, Antinuclear; Autoimmune Diseases; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Graft vs Host Disease; Mice; Mice, Inbred MRL lpr; Nephritis; Proteinuria; Quinolines; Structure-Activity Relationship

A series of quinoline-3-carbothioamides and their analogues was prepared via four synthetic routes and evaluated for their antinephritic and immunomodulating activities. The optimal compound 9g strongly inhibited the T-cell independent antibody production in mice immunized with TNP-LPS and was highly effective in two nephritis models, namely chronic graft-versus-host disease and autoimmune MRL/l mice.

Topics: Adjuvants, Immunologic; Administration, Oral; Animals; Antibody Formation; Autoimmune Diseases; Disease Models, Animal; Dogs; Graft vs Host Disease; Half-Life; Immunization; Mice; Nephritis; Proteinuria; Quinolines; Structure-Activity Relationship; Thioamides

The effect of linomide, an immunomodulatory drug, on natural killer (NK) cells and T cell-dependent immune responses following syngeneic or allogeneic bone marrow transplantation (BMT) was investigated in BALB/c mice inoculated with B-cell leukemia (BCL1). Linomide given in the drinking water had no impact on graft survival or graft versus leukemia (GVL) effects. Although linomide regulates anti-self reactivity in mice with experimental and spontaneous autoimmune disorders, the anti-tumor effects induced by allogeneic donor lymphocytes were not affected. This indicates that different mechanisms regulate anti-self and anti-leukemia effects. Alternatively, linomide might affect the homing of self-reactive lymphocytes to specific target organs in autoimmune disorders, although the homing process may not be relevant to the control of leukemia by alloreactive lymphocytes.

Topics: Adjuvants, Immunologic; Animals; Bone Marrow Transplantation; Dose-Response Relationship, Drug; Female; Graft vs Host Disease; Graft vs Leukemia Effect; Hydroxyquinolines; Killer Cells, Natural; Leukemia, B-Cell; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL

Roquinimex (Linomide) is an immunotherapeutic agent used in conjunction with autologous bone marrow transplantation (ABMT) for treatment of acute and chronic myelogenous leukemia (AML and CML). This agent may induce graft-versus-host reactions (GVHR) as well as graft-versus-leukemia (GVL) effects.. We documented the incidence of acute cutaneous GVHR associated with roquinimex immunotherapy. The presence or absence of autologous GVHR was also correlated with a potential GVL effect in patients with CML treated with ABMT and subsequent roquinimex immunotherapy in the period after the transplant.. Fifteen patients undergoing bone marrow transplantation and roquinimex immunotherapy for CML were followed up, and clinicopathologic data were analyzed.. Acute cutaneous GVHRs were observed in 6 of 15 patients (40%) treated with roquinimex. Ten of 11 evaluable patients receiving roquinimex exhibited eccrine sweat gland necrosis (ESGN) (90.9%), which was independent of the acute GVHR. Neither bone marrow engraftment status nor the survival rates of patients with and without GVHR was significantly different.. Roquinimex immunotherapy enhances the incidence of GVHR and was associated with a high rate of ESGN in patients with CML who were undergoing ABMT. There was no significant association between ESGN and acute GVHR. Acute autologous GVHR caused by roquinimex did not correlate with a GVL effect in our study of 15 patients with CML.

Topics: Adjuvants, Immunologic; Adult; Bone Marrow Transplantation; Female; Graft vs Host Disease; Graft vs Leukemia Effect; Humans; Hydroxyquinolines; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Necrosis; Sweat Gland Diseases; Transplantation, Autologous

Topics: Adjuvants, Immunologic; Antibodies, Monoclonal; Graft vs Host Disease; Humans; Hydroxyquinolines; Immunotherapy; Interleukin-2; Leukemia, Myeloid, Acute; Leukocyte Transfusion; Neoplasm, Residual

Topics: Adjuvants, Immunologic; Autoimmune Diseases; Bone Marrow Transplantation; Graft vs Host Disease; Humans; Hydroxyquinolines; Immunosuppression Therapy; Immunotherapy; Lymphocyte Depletion; T-Lymphocytes; Transplantation, Homologous

The effects of the immunomodulating substance LS-2616 (linomide) on graft-versus-host reaction (GVHR) were investigated in a semi-syngeneic small bowel transplantation model. The entire bowel of Lewis donors were transplanted heterotopically into (Lewis x BN) F1 hybrids. Both untreated animals and animals treated with LS-2616, in a daily dose of 160 mg/kg, developed a lethal GVHR. The median survival time in untreated animals was 14.5 days while in LS-2616 treated animals it was just eight days (p < 0.01). LS-2616 in combination with cyclosporin A (CyA), 15 mg/kg given orally on days 0-20, did not seem to alter the survival times compared with CyA treatment alone; 56% of the animals treated with CyA survived for more than 100 days and after combined treatment with CyA/LS-2616 there were 50% permanent survivors. Also the effect of earlier sensitization of the donor on the course of GVHR was investigated. Hearts from BN rats were transplanted heterotopically to the neck vessels of Lewis rats. The hearts were rejected on about day six; five days later the bowels were harvested and transplanted into (Lewis x BN) F1 hybrids. The median survival time in this group was 12.5 days. Taken together our results, in combination with earlier findings, suggest that, at the level of effector mechanisms, GVHR is not an exact mirror image of rejection. Also, LS-2616 appears to be a useful tool for further studies of the mechanisms of action of GVHR.

Topics: Adjuvants, Immunologic; Animals; Cyclosporine; Drug Administration Schedule; Graft vs Host Disease; Graft vs Host Reaction; Heart Transplantation; Hydroxyquinolines; Interleukin-2; Intestine, Small; Male; Molecular Structure; Rats; Rats, Inbred BN; Rats, Inbred Lew; Stimulation, Chemical; T-Lymphocytes; Transplantation, Heterotopic

Topics: Adult; Carcinoma; Child, Preschool; Dermatofibrosarcoma; Drug Eruptions; Female; Graft vs Host Disease; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Granuloma; Hidradenitis; Histiocytosis, Sinus; Humans; Hydroxyquinolines; Lymphatic Diseases; Male; Middle Aged; Myxedema; Nevus; Paraproteinemias; Skin Diseases; Syphilis; Xanthomatosis