Reduction of Postischemic Immune Inflammatory Response: An Effective Strategy for Attenuating Chronic Allograft Nephropathy

Herrero‐Fresneda, Immaculada; Torrás, Joan; Vidal, August; Lloberas, Núria; Cruzado, Josep M.; Grinyó, Josep M.

doi:10.1097/01.tp.0000147198.88801.57

Cited by 20 publications

(18 citation statements)

References 35 publications

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“…1 Our model was previously described as 'humoral-like' as it displays vascular damage with fibrinoid necrosis and perivascular edema. 21 Now we confirm that in this model, in which pre-transplant DSA were not present in WA rats, there was a massive formation of DSA probably due to early peri-transplant B-cell activation. [25][26][27] In this highly stringent model, intra-graft CD40 silencing was unable per se to reduce circulating DSA, as expected from local treatment.…”

Section: Discussionsupporting

confidence: 73%

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In vivo therapeutic efficacy of intra-renal CD40 silencing in a model of humoral acute rejection

et al. 2011

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The humoral branch of the immune response has an important role in acute and chronic allograft dysfunction. The CD40/CD40L costimulatory pathway is crucial in B-and T-alloresponse. Our group has developed a new small interfering RNA (siRNA) molecule against CD40 that effectively inhibits its expression. The aim of the present study was to prevent rejection in an acute vascular rejection model of kidney transplant by intra-graft gene silencing with anti-CD40 siRNA (siCD40), associated or not with sub-therapeutic rapamycin. Four groups were designed: unspecific siRNA as control; sub-therapeutic rapamycin; siCD40; and combination therapy. Long-surviving rats were found only in both siCD40-treated groups. The CD40 mRNA was overexpressed in control grafts but treatment with siCD40 decreased its expression. Recipient spleen CD40+ B-lymphocytes were reduced in both siCD40-treated groups. Moreover, CD40 silencing reduced donor-specific antibodies, graft complement deposition and immune-inflammatory mediators. The characteristic histological features of humoral rejection were not found in siCD40-treated grafts, which showed a more cellular histological pattern. Therefore, the intra-renal effective blockade of the CD40/CD40L signal reduces the graft inflammation as well as the incidence of humoral vascular acute rejection, finally changing the type of rejection from humoral to cellular. Gene Therapy (2011) 18, 945-952;

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Section: Discussionsupporting

confidence: 73%

“…21 As Sacks and Zhou suggested 22 , donor kidney pre-treatment appears as a valid strategy to modify the sensitivity of donor kidneys, and may have application in human renal therapy. Our present strategy using intra-graft CD40 silencing reduces the humoral vascular acute rejection incidence, shifting towards a cellular rejection pattern.…”

Section: Discussionmentioning

confidence: 99%

In vivo therapeutic efficacy of intra-renal CD40 silencing in a model of humoral acute rejection

et al. 2011

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“…In addition, clinical studies revealed an equivalent inflammation in human graft muscularis with impaired contractile activity early after SBTx (15). As early inflammation in the graft can result in chronic functional graft failure (16,17) …”

Section: Small Bowel Transplantation (Sbtx) Is the Only Definitive Trmentioning

confidence: 99%

Influence of Immunosuppression on Alloresponse, Inflammation and Contractile Function of Graft After Intestinal Transplantation

Fujishiro

Pech

Finger

et al. 2010

American Journal of Transplantation

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In small bowel transplantation (SBTx), graft manipulation, ischemia/reperfusion injury and acute rejection initiate a severe cellular and molecular inflammatory response in the muscularis propria leading to impaired motility of the graft. This study examined and compared the effect of tacrolimus and sirolimus on inflammation in graft muscularis. After allogeneic orthotopic SBTx, recipient rats were treated with tacrolimus or sirolimus. Tacrolimus and sirolimus attenuated neutrophilic, macrophage and T-cell infiltration in graft muscularis, which was associated with reduced apoptotic cell death. Nonspecific inflammatory mediators (IL-6, MCP-1) and T-cell activation markers (IL-2, IFNc ) were highly upregulated in allogeneic control graft muscularis 24 h and 7 days after SBTx, and tacrolimus and sirolimus significantly suppressed upregulation of these mediators. In vitro organ bath method demonstrated a severe decrease in graft smooth muscle contractility in allogeneic control (22% of normal control). Correlating with attenuated upregulation of iNOS, tacrolimus and sirolimus treatment significantly improved contractility (64% and 72%, respectively). Although sirolimus reduced cellular and molecular inflammatory response more efficiently after 24 h, contrary tacrolimus prevented acute rejection more efficiently. In conclusion, tacrolimus and sirolimus attenuate cellular and molecular inflammatory response in graft muscularis and subsequent dysmotility of the graft after allogeneic SBTx.

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“…For renal transplantation, inbred male Lewis rats (MHC haplotype: RT1 I ) (250 g body weight; Charles River) received a kidney from male Fischer-344 rats (MHC haplotype: RT1 Iv1 ) (250 g body weight, Charles River) as previously described [12][13][14]. Briefly, kidneys were 2.5 h preserved in EuroCollins at 4°C.…”

Section: Rat Kidney Transplantationmentioning

confidence: 99%

Mesenchymal Stem Cell Therapy Prevents Interstitial Fibrosis and Tubular Atrophy in a Rat Kidney Allograft Model

Franquesa

Herrero

Torras

et al. 2012

Stem Cells and Development

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125

100

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In solid organ transplantation, mesenchymal stem cell (MSC) therapy is strongly emerging among other cell therapies due to the positive results obtained in vitro and in vivo as an immunomodulatory agent and their potential regenerative role. We aimed at testing whether a single dose of MSCs, injected at 11 weeks after kidney transplantation for the prevention of chronic mechanisms, enhanced regeneration and provided protection against the inflammatory and fibrotic processes that finally lead to the characteristic features of chronic allograft nephropathy (CAN). Either bone marrow mononuclear cells (BMCs) injection or no-therapy (NT) were used as control treatments. A rat kidney transplantation model of CAN with 2.5 h of cold ischemia was used, and functional, histological, and molecular parameters were assessed at 12 and 24 weeks after transplantation. MSC and BMC cell therapy preserves renal function at 24 weeks and abrogates proteinuria, which is typical of this model (NT24w: 68.9 -26.5 mg/24 h, MSC24w: 16.6 -2.3 mg/24 h, BMC24w: 24.1 -5.3 mg/24 h, P < 0.03). Only MSC-treated animals showed a reduction in interstitial fibrosis and tubular atrophy (NT24w: 2.3 -0.29, MSC24w: 0.4 -0.2, P < 0.03), less T cells (NT: 39.6 -9.5, MSC: 8.1 -0.9, P < 0.03) and macrophages (NT: 20.9 -4.7, MSC: 5.9 -1.7, P < 0.05) infiltrating the parenchyma and lowered expression of inflammatory cytokines while increasing the expression of anti-inflammatory factors. MSCs appear to serve as a protection from injury development rather than regenerate the damaged tissue, as no differences were observed in Ki67 expression, and kidney injury molecule-1, Clusterin, NGAL, and hepatocyte growth factor expression were only up-regulated in nontreated animals. Considering the results, a single delayed MSC injection is effective for the long-term protection of kidney allografts.

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Reduction of Postischemic Immune Inflammatory Response: An Effective Strategy for Attenuating Chronic Allograft Nephropathy

Cited by 20 publications

References 35 publications

In vivo therapeutic efficacy of intra-renal CD40 silencing in a model of humoral acute rejection

In vivo therapeutic efficacy of intra-renal CD40 silencing in a model of humoral acute rejection

Influence of Immunosuppression on Alloresponse, Inflammation and Contractile Function of Graft After Intestinal Transplantation

Mesenchymal Stem Cell Therapy Prevents Interstitial Fibrosis and Tubular Atrophy in a Rat Kidney Allograft Model

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