Effects of local cryotherapy on systemic endothelial activation, dysfunction, and vascular inflammation in adjuvant-induced arthritis (AIA) rats.

AIM: This study explored the systemic vascular effects of local cryotherapy with a focus on endothelial changes and arterial inflammation in the model of rat adjuvant-induced arthritis (AIA). METHODS: Cryotherapy was applied twice a day on hind paws of AIA rats from the onset of arthritis to the acute inflammatory phase. Endothelial activation was studied in the aorta by measuring the mRNA levels of chemokines (CXCL-1, MCP-1 (CCL-2), MIP-1α (CCL-3)) and adhesion molecules (ICAM-1, VCAM-1) by qRT-PCR. Endothelial dysfunction was measured in isolated aortic and mesenteric rings. Aortic inflammation was evaluated via the mRNA expression of pro-inflammatory cytokines (TNF-α, IL-6) by qRT-PCR and leucocyte infiltration analysis (flow cytometry). Plasma levels of TNF-α, IL-6, IL-1ß, IL-17A, and osteoprotegerin (OPG) were measured using Multiplex/ELISA. RESULTS: AIA was associated with an increased aortic expression of CXCL-1 and ICAM-1 as well as an infiltration of leucocytes and increased mRNA expression of IL-6, IL-1ß, and TNF-α. Local cryotherapy, which decreased arthritis score and structural damages, reduced aortic mRNA expression of CXCL-1, IL-6, IL-1ß, and TNF-α, as well as aortic infiltration of leucocytes (T lymphocytes, monocytes/macrophages, neutrophils) and improved acetylcholine-induced vasorelaxation in the aorta and mesenteric arteries. Plasma levels of IL-17A and OPG were significantly reduced by cryotherapy, while the number of circulating leucocytes was not. IL-17A levels positively correlated with endothelial activation and dysfunction. CONCLUSION: In the AIA model, local cryotherapy reduced systemic endothelial activation, immune cell infiltration, and endothelial dysfunction. Mechanistically, the reduction of circulating levels of IL-17A appears as the possible link between joint cooling and the remote vascular effects.

Saturation of the Inverse Cascade in Surface Gravity-Wave Turbulence.

We report on the observation of surface gravity-wave turbulence at scales larger than the forcing ones in a large basin. In addition to the downscale transfer usually reported in gravity-wave turbulence, an upscale transfer is observed, interpreted as the inverse cascade of weak turbulence theory. A steady state is achieved when the inverse cascade reaches a scale in between the forcing wavelength and the basin size, but far from the latter. This inverse cascade saturation, which depends on the wave steepness, is probably due to the emergence of nonlinear dissipative structures such as sharp-crested waves.

In-vitro validation of 4D flow MRI measurements with an experimental pulsatile flow model.

PURPOSE: The purpose of this study was to assess the precision of four-dimensional (4D) phase-contrast magnetic resonance imaging (PCMRI) to measure mean flow and peak velocity (Vmax) in a pulsatile flow phantom and to test its sensitivity to spatial resolution and Venc. MATERIAL AND METHODS: The pulsatile flow phantom consisted of a straight tube connected to the systemic circulation of an experimental mock circulatory system. Four-dimensional-PCMR images were acquired using different spatial resolutions (minimum pixel size: 1.5×1.5×1.5mm3) and velocity encoding sensitivities (up to three times Vmax). Mean flow and Vmax calculated from 4D-PCMRI were compared respectively to the reference phantom flow parameters and to Vmax obtained from two-dimensional (2D)-PCMRI. RESULTS: 4D-PCI measured mean flow with a precision of -0.04% to+5.46%, but slightly underestimated Vmax when compared to 2D-PCMRI (differences ranging from -1.71% to -3.85%). 4D PCMRI mean flow measurement was influenced by spatial resolution (P<0.001) with better results obtained with smaller voxel size. There was no effect of Venc on mean flow measurement. Regarding Vmax, neither spatial resolution nor Venc did influence the precision of the measurement. CONCLUSION: Using an experimental pulsatile flow model 4D-PCMRI is accurate to measure mean flow and Vmax with better results obtained with higher spatial resolution. We also show that Venc up to 3 times higher than Vmax may be used with no effect on these measurements.

IL-22 deficiency in donor T cells attenuates murine acute graft-versus-host disease mortality while sparing the graft-versus-leukemia effect.

Acute graft-versus-host disease (aGVHD) remains a major complication following allogeneic hematopoietic cell transplantation (allo-HCT), limiting the success of this therapy. Many proinflammatory cytokines secreted following the conditioning regimen have been linked to aGVHD initiation. Interleukin-22 (IL-22) is a cytokine related to IL-10 for its structure and is secreted by T helper type 17 (TH17) cells and innate immune cells. Given the paradoxical role of IL-22 in inflammation with both protective or proinflammatory functions, we investigated whether IL-22 could have a role in aGVHD pathophysiology in a mouse allo-HCT model. In this study, we show that IL-22 deficiency in donor T cells can decrease the severity of aGVHD, while limiting systemic and local inflammation in aGVHD target organs. In addition, we found that Foxp3+ regulatory T cells (Treg cells) were increased in recipient mice that received IL-22-deficient T cells, suggesting that Treg were involved in the reduced severity of GVHD. Finally, we found that the graft-versus-leukemia (GVL) effect mediated by donor T cells was preserved in the absence of IL-22. Overall, these data suggest that targeting of IL-22 may represent a valid approach towards decreasing aGVHD severity after allo-HCT while preserving the GVL effect.

Intravenous infusion of donor apoptotic leukocytes before transplantation delays allogeneic islet graft rejection through regulatory T cells.

AIM: This study describes the ability of intravenous donor apoptotic leukocyte infusion before islet transplantation to delay allogeneic graft rejection and implicates regulatory T cells (T(reg)) in the effect. METHODS: Allogeneic FVB (Friend virus B-type) islet transplants were placed under the kidney capsule of BALB/c recipient mice rendered diabetic by streptozotocin. Apoptotic donor leukocytes were infused intravenously 7 days before transplantation. Foxp3/DTR/GFP transgenic C57BL/6 mice were used as recipients to show depletion of T(reg) after apoptotic cell infusion. Control mice received islet transplants without apoptotic cells. RESULTS: The graft median survival time (MST) in recipient mice was 15±1.5 days when apoptotic cells were infused 7 days prior to transplantation of a 1000-islet-containing allograft and 6±0.5 days in the control mice (P<0.01). The same effect was observed using a 500-islet allograft, with an MST of 9±1.1 days vs. 3±0.8 days with and without (controls) apoptotic cells, respectively (P<0.01). This immunomodulatory effect was not observed when apoptotic cell administration was performed on the day of transplantation. Specific T(reg) depletion in Foxp3/DTR/GFP recipient mice inhibited the beneficial effect of apoptotic cell infusion with an MST of 8±1.5 days after apoptotic cell infusion vs. 2±0.2 days when T(reg) were depleted (P<0.01). Furthermore, T(reg) were specifically detected in the islet grafts of mice infused with apoptotic cells prior to islet transplantation. CONCLUSION: Infusion of donor apoptotic cells 7 days before allogeneic transplantation delays islet allograft rejection through a process involving T(reg).

[Organ transplantation and blood transfusion]. / Transfusion sanguine et transplantation.

Pretransplant blood transfusion remains a controversial subject and its history can summarize the last 40 years of transplantation. Until 1971, transfusions were widely used in patients awaiting transplantation, especially due to the anemia induced by the chronic renal dysfunction. Then, a noxious effect of preformed anti-HLA antibodies on renal grafts survival was reported and pretransplant transfusions were stopped. Between 1972 and 1977, improvement of renal graft survival in patients who received pretransplant transfusions was noted. Therefore, from 1978 on, a systematic policy of pretransplant transfusions was adopted by almost all centres of transplantation. During the eighties, it was again abandoned for several reasons: absence of graft survival improvement in patients treated by cyclosporine, HLA immunization leading to an increased incidence of acute graft rejection, risk of viral diseases transmission and human recombinant erythropoietin development. The lack of improvement in graft survival for ten years has been leading the transplant community to look for antigen-specific immunosuppressive strategies to achieve transplantation tolerance. Donor-specific transfusion may have clinical benefits, as long-term grafts survival improvement, through modulation of the recipient's cellular immune system and has been recently reconsidered, especially before living donor transplantation. The immunological mechanisms inducing a tolerance-gaining effect of transfusions are still misunderstood, but the recent discovery of immunomodulatory effects of the apoptotic cells present in cellular products could enlighten our comprehension of pretransplant transfusions benefits and could help to develop specific tolerance induction strategies in solid organ transplantation.

[Towards the use of intravenous apoptotic leukocyte infusion as a cell-based therapy approach?]. / Vers l'utilisation thérapeutique de l'administration intraveineuse de leucocytes apoptotiques du donneur en thérapie cellulaire ?

In the past few years, significant advances have been performed in the field of cell-based therapies. This concerns mainly regenerative medicine with the use of stem cells, as well as the modulation of immune responses. In order to modulate allogeneic immune responses after transplantation, we have developed a cell therapy approach based on the immunomodulatory properties of intravenous donor apoptotic cell infusion. In allogeneic hematopoietic cell transplantation settings, we reported that intravenous apoptotic leukocyte infusion, simultaneously to allogeneic bone marrow grafts, favors hematopoietic engraftment, prevents alloimmunization and delays graft-versus-host disease. Here, we review the different factors and cells implicated in the immunomodulatory properties of apoptotic cells. Then, we discuss the potential significance of such observations in transfusion practice.