Downregulation of Both Interleukin-12 and Interleukin-2 in Heart Allografts by Pretransplant Host Treatment With Granulocyte Colony-Stimulating Factor and Tacrolimus

Egi, Hiroyuki; Hayamizu, Keisuke; Kitayama, Tomoya; Ohmori, Ichiro; Okajima, Masazumi; Asahara, Toshimasa

doi:10.1006/cyto.2002.0887

Cited by 15 publications

(4 citation statements)

References 16 publications

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“…By the same reasoning, patients with lower IL‐12 would be expected to have a less aggressive immune response, a conclusion supported by our data and by recent studies demonstrating that patients with low preoperative IL‐12 levels had higher rates of post‐operative sepsis. Lowering IL‐12 before transplantation might improve tolerance of an allograft, a theory supported by a previous study by Egi et al., in which pre‐transplant reduction of IL‐12 in a murine model of cardiac transplantation lowered the incidence of acute rejection (13). Despite the fact that IL‐10 is known to be an anti‐inflammatory cytokine, pre‐transplant elevations of IL‐10 predicted rejection in a similar fashion to IL‐12 in this study.…”

Section: Discussionmentioning

confidence: 81%

Pre‐transplant elevations of interleukin‐12 and interleukin‐10 are associated with acute rejection after renal transplantation

Fitzgerald

Johnson

Perez

2004

Clinical Transplantation

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Section: Discussionmentioning

confidence: 81%

Pre‐transplant elevations of interleukin‐12 and interleukin‐10 are associated with acute rejection after renal transplantation

Fitzgerald

Johnson

Perez

2004

Clinical Transplantation

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Section: Cyclophilin-mediated Inhibition Of Il-12 Productionmentioning

confidence: 99%

“…Tacrolimus is utilized in bone marrow transplantation to prevent graftversus-host disease. It appeared to suppress production of Th1 cytokines including IL-12 in LPS-stimulated myeloid dendritic cells (Szabo et al 2001) and in heart allografts (Egi et al 2002). Dendritic cells derived from CD34 ‡ haematopoietic progenitor cells cultured in the presence of tacrolimus showed significantly lower IL-12 production, and were capable of inducing IL-4 production in a CD4 ‡ T cell line (Shimuzu et al 2000).…”

Section: Cyclophilin-mediated Inhibition Of Il-12 Productionmentioning

confidence: 99%

Inhibiting cytokines of the interleukin-12 family: recent advances and novel challenges

Vandenbroeck

Alloza

Gadina³

et al. 2004

Journal of Pharmacy and Pharmacology

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Interleukin-12 (IL-12) and the more recently discovered IL-23 and IL-27 constitute a unique family of structurally related, heterodimeric cytokines that regulate cell-mediated immune responses and T helper 1 (Th1)-type inflammatory reactions. Not surprisingly, the potentiality of treating conditions such as multiple sclerosis (MS) and rheumatoid arthritis (RA) through pharmacological interference with IL-12 pathways has received widespread attention. In this review we have examined over 50 substances with reported IL-12 inhibitory effects. We demonstrate that a majority of these belong to a limited number of major functional classes, each of which targets discrete events in the IL-12 biological pathway. Thus, most IL-12 inhibitory substances appear to work either through inhibition of transcription factor NF-µB activation, up-regulation of intracellular cAMP, blockage of posttranslational processing or interference with signal transduction pathways. In addition, cyclophilinbinding drugs, and generic inhibitors of nuclear histone deacetylases, and of ion channels, pumps and antiporters are emerging as potential leads to novel targets for interference with IL-12 production. Many inhibitors of NF-µB and of IL-12 signal transduction have been proven effective in limiting or preventing disease in experimental autoimmune encephalomyelitis (EAE) models of MS. The sharing of the p40 subunit, the IL-12R 1 and components of the signal transduction pathways between IL-12 and IL-23 raises the question as to whether the beneficial effects of various drugs previously ascribed to inhibition of IL-12 may, in fact, have been due to concurrent blockage of both cytokines, or of IL-23, rather than IL-12. Moreover, the homodimeric 2 -form of IL-12, though originally considered to display only antagonistic effects, is now emerging as a pronounced agonist in a variety of inflammatory processes. Reassessment of IL-12 inhibitory compounds is therefore needed to scrutinize their effects on IL-12 ¬ , 2 and IL-23 formation. This is likely to open exciting perspectives to the identification of drugs that target these cytokines either indiscriminately or selectively. The functional diversity of presently available inhibitors should facilitate an unprecedented flexibility in designing future trials for the treatment of IL-12-and IL-23-mediated disorders.

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“…The rhG‐CSF has an influence at least indirectly through inducing type‐2 immune cells (DC2, Th2), which down‐regulate production by type‐1 cells of rejection‐associated cytokines such as IFN‐ γ , IL‐2, TNF‐ α , and IL‐12. Egi et al reported that IL‐12p35 expression was greatly inhibited by rhG‐CSF treatment in heart allografts by pretransplant host treatment (35). On the other hand, in the same rat heart allograft model, IL‐12 p40 was up‐regulated by rhG‐CSF‐treated allogeneic blood transfusion but down‐regulated by transfusion of rhG‐CSF‐treated isogeneic blood (36).…”

Section: Discussionmentioning

confidence: 99%

Effect of granulocyte colony‐stimulating factor on IL‐12 p40 production during chemotherapy for B‐cell lineage non‐Hodgkin's lymphoma patients

Toubai¹,

Tanaka²,

Ota³

et al. 2006

European J of Haematology

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IL-12 is a 70-kDa cytokine comprised of two disulfide-linked proteins (p35 and p40) and is essential for the initiation of effective immune response. Granulocyte-colony stimulating factor (G-CSF) affects the balance in the production of anti-inflammatory cytokines. We investigated the serum IL-12 p40 and IL-12 Mix (p40 and p70) production in 28 patients with B-cell lineage non-Hodgkin's lymphoma (NHL) treated with chemotherapy (e.g., CHOP regimen) with or without G-CSF administration and 8 healthy volunteers. We found that serum levels of IL-12 p40 (191.2±150.0 pg/ml) and IL-12 Mix (277.4 ±274.5 pg/ml) in the patients before chemotherapy were higher than those in the healthy volunteers (IL-12 p40: 76.4±25.3 pg/ml, IL-12 Mix:48.5±33.4 pg/ml) (p=0.04 and 0.02, respectively). Next, we examined the serum IL-12 p40 and Il-12 Mix levels in 9 patients receiving chemotherapy with administration of G-CSF (CG group, n=9) and without G-CSF (C group, n=9). Serum IL-12 p40 and IL-12 Mix levels were decreased on 10 days after chemotherapy in both groups, and those in CG groups were significantly lower than those in C group. These results indicated that administration of G-CSF decreased serum IL-12 p40 and IL-12 Mix levels. Overall survival (OS) at 24 months was not significantly different in the two groups (58.3% in group C vs 80.0% in group CG, P=0.67). However, the survival rate of patients at clinical stages Ⅲ and Ⅳ in CG group (n=6, 66.0%) was significantly better than that of patients in C group (n=4, 25.0%) (p=0.02). Long-term administration of G-CSF appears to influence the survival rate by reducing immunosuppressive IL-12 p40 production.

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Downregulation of Both Interleukin-12 and Interleukin-2 in Heart Allografts by Pretransplant Host Treatment With Granulocyte Colony-Stimulating Factor and Tacrolimus

Cited by 15 publications

References 16 publications

Pre‐transplant elevations of interleukin‐12 and interleukin‐10 are associated with acute rejection after renal transplantation

Pre‐transplant elevations of interleukin‐12 and interleukin‐10 are associated with acute rejection after renal transplantation

Inhibiting cytokines of the interleukin-12 family: recent advances and novel challenges

Effect of granulocyte colony‐stimulating factor on IL‐12 p40 production during chemotherapy for B‐cell lineage non‐Hodgkin's lymphoma patients

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