Predominant expression of the Th2 response in chronic cardiac allograft rejection

Mhoyan, Ann; Wu, Guey-Shuang; Kakoulidis, Thanos P.; Que, Xingyi; Yolcu, Esma S.; Cramer, Donald V.; Shirwan, Haval

doi:10.1111/j.1432-2277.2003.tb00350.x

Cited by 21 publications

(20 citation statements)

References 41 publications

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“…The TGF-β C-del showed a marginal signifi cance and the frequency of low producing genotype C/CC of TGF-β showed 2.6-fold risk. Our fi ndings showing higher frequency of rejection episode in recipients having high producing genotype (B1B1) of IL-4 corroborate the previous observation, which opined that Th2 cytokines promote both acute and chronic allograft rejection (Mhoyan et al 2003). IL-4 VNTR, intron 3 has not been previously reported in renal transplant patients.…”

Section: Discussionsupporting

confidence: 82%

Association of pro/anti-inflammatory cytokine gene variants in renal transplant patients with allograft outcome and cyclosporine immunosuppressant levels

Manchanda

Kumar²,

Sharma³

et al. 2008

BTT

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T-helper (Th) type 1/Th2 cytokines are key mediators in induction/effecter phases of all immune and infl ammatory responses playing role in acute/chronic renal allograft rejection. Association studies lead to identifi cation of patient risk profi les enabling individualization of level of immunosuppressions. We investigated the association of allograft rejection with interleukin-2 (IL-2), IL-4, IL-6, tumor necrosis factor-α (TNF-α) -308, transforming growth factor-β (TGF-β) (C-del, codon 10 and 25) gene variants in 184 renal transplant recipients and 180 controls. These cytokine genotypes were also evaluated with cyclosporine levels (C2) at one month in 135 stable recipients. High producing genotypes B1B1 of IL-4 and AA of TNF-α −308 showed signifi cant association with rejection of allograft. The dose-adjusted C2 levels were signifi cantly lower in patients with the high producing genotype T/T of IL-2 and heterozygous G/C of TGF-β codon 25 (P = 0.012 and 0.010, respectively). Haplotype frequencies were comparable in subjects for TGF-β codon-10 and 25. Combined inter-gene interaction showed high risk for rejection in recipients with high producing genotype B1B1 of IL-4 and AA of TNF-α and high TNF-α (AA) with low TGF-β (CC or Pro/Pro). In conclusion, association of IL-4 VNTR and TNF-α -308 suggested the involvement of these cytokines contributing to pathogenesis of allograft rejection. Recipients with TT genotype of IL-2 and GC of TGF-β codon 25 having low C2 levels may require higher cyclosporine dosage. Combined analysis of gene-gene interaction demonstrated synergistic effect of cytokines increasing risk for rejection. Thus, this information may help in pre-assessment of allograft outcome and to optimize cyclosporine therapy in post-transplant patients.

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Section: Discussionsupporting

confidence: 82%

Association of pro/anti-inflammatory cytokine gene variants in renal transplant patients with allograft outcome and cyclosporine immunosuppressant levels

Manchanda

Kumar²,

Sharma³

et al. 2008

BTT

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“…We conclude that detection of a DDR-DTH response to donor antigens, ostensibly a regulatory T cell response, does not identify a kidney or simultaneous kidney/pancreas recipient that has acquired a robust tolerance to their allograft(s). Further, the DDR-DTH positive recipients are significantly more likely to develop detectable anti-MHC alloantibodies ( Figure 5), perhaps a requisite consequence of the development of a Th2-type, anti-inflammatory response to donor alloantigens as reported in the rat cardiac transplant model (18). Consequently, reduction in immunosuppression or complete withdrawal in patients displaying the DDR-DTH phenotype appears inadvisable.…”

Section: Discussionmentioning

confidence: 84%

Evaluation of immune regulation in transplant patients using the trans vivo delayed type hypersensitivity assay

et al. 2007

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Allograft recipient IL-10 and/or TGFb dependent anti-inflammatory T cell delayed type hypersensitivity (DTH) responses to donor derived antigens, or regulatory T cell responses, have been demonstrated in rodents and transplant patients using a previously described trans-vivo DTH assay. We employed this assay to determine the incidence of recipient anti-inflammatory T cell responses to donor antigens in a large cohort (n=420) of primary kidney and simultaneous kidneypancreas transplant patients tested a mean of 4.8 years after transplantation. The results were compared with clinical outcomes and the presence of detectable circulating alloantibodies. We found an unexpectedly high incidence (21.9%) of this anti-inflammatory T cell response to donor antigens in these recipients. There was a significant correlation between this T cell phenotype and the presence of detectable circulating alloantibodies (p=0.03). There was no correlation between this T cell phenotype and the degree of HLA mismatch. Additionally, the presence of an anti-inflammatory DTH response to donor antigens did not correlate with an improved clinical outcome at a median of nearly 5 years after transplantation. These findings suggest that detection of an anti-inflammatory T cell response to donor antigens does not identify patients that have developed graft protective, regulatory T cell responses.

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“…Although the underlying mechanisms are poorly understood, we believe that TIAF1 may regulate the TH2 response, by either regulating cytokine production or TH2 cell proliferation, which leads to chronic allograft rejection. TH2-derived inflammatory cytokines contribute in part to chronic allograft rejection (Kist- Van Holthe et al, 2002;Le Moine et al, 2002;Otto et al, 2002;Sun et al, 2003;Mhoyan et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

TIAF1 and p53 Functionally Interact in Mediating Apoptosis and Silencing of TIAF1 Abolishes Nuclear Translocation of Serine 15-Phosphorylated p53

Schultz

Khera

Sleve

et al. 2004

DNA and Cell Biology

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TIAF1 is a TGF-beta 1-induced factor that protects L929 fibroblasts from TNF-mediated apoptosis. In contrast, overexpressed TIAF1 induces growth inhibition and apoptosis of monocytic U937 and various nonfibroblast cells. TIAF1-mediated apoptosis of U937 cells involves upregulation of p53, p21, and Smad2/4, but downregulation of ERK phosphorylation. To determine whether p53 and TIAF1 functionally interact in regulating cell death, ectopic TIAF1 and p53 were shown to induce apoptosis of U937 cells in both synergistic and antagonistic manners. At optimal levels both TIAF1 and p53 mediated apoptosis cooperatively. Also, both proteins suppressed adherence-independent growth of L929 cells. In contrast, initiation of apoptosis by overexpressed TIAF1 was blocked by low doses of p53, and vice versa. Furthermore, ectopic p53 blocked an ongoing apoptosis in U937 cells stably expressing TIAF1. Yeast two-hybrid analyses failed to demonstrate the binding of p53 with TIAF1, suggesting an unidentified protein that links the p53/TIFA1 interaction. Suppression of TIAF1 expression by siRNA could not inhibit Ser15 phosphorylation in p53 in response to UV and etoposide. However, nuclear translocation of these Ser15-phosphorylated p53 was significantly reduced in TIAF1-silenced cells. Taken together, TIAF1 and p53 functionally interact in regulating apoptosis, and TIAF1 is likely to participate in the nuclear translocation of activated p53.

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Predominant expression of the Th2 response in chronic cardiac allograft rejection

Cited by 21 publications

References 41 publications

Association of pro/anti-inflammatory cytokine gene variants in renal transplant patients with allograft outcome and cyclosporine immunosuppressant levels

Association of pro/anti-inflammatory cytokine gene variants in renal transplant patients with allograft outcome and cyclosporine immunosuppressant levels

Evaluation of immune regulation in transplant patients using the trans vivo delayed type hypersensitivity assay

TIAF1 and p53 Functionally Interact in Mediating Apoptosis and Silencing of TIAF1 Abolishes Nuclear Translocation of Serine 15-Phosphorylated p53

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