Involvement of the programmed death-1/programmed death-1 ligand pathway in CD4+CD25+ regulatory T-cell activity to suppress alloimmune responses

BACKGROUND: Immune regulatory CD4+CD25+ T (regulatory T; Treg) cells play a vital role in the induction and maintenance of self-tolerance. They are essential for the homeostasis of T cells, the prevention of autoimmunity, and the induction of tolerance to allogeneic donor grafts. However, the underlying mechanism of their functions remains mostly elusive. Therefore, we investigated here a crucial role of Treg cells in their response to alloantigen via the programmed death (PD)-1/PD-1 ligand (PD-L1) pathway. METHODS: In vitro mixed lymphocyte reaction (MLR) assay, graft-versus-host disease (GvHD) and a skin transplantation model were used to evaluate the mechanisms of PD-1/PD-L1 pathway. RESULTS: Blockade of the PD-1/PD-L1 pathway using anti-PD-L1 monoclonal antibodies (mAb) is found to inhibit Treg cell's ability to suppress and restore CD4+CD25-T-cell proliferation in vitro. GvHD was lethal after adoptive transfer of allogeneic C57BL/6 (H-2K) spleen cells to NOD/SCID (H-2K) mice unless CD25+ T cells were also included. Strikingly, the suppression of GvHD by CD25+ cells was abrogated by anti-PD-L1 mAb administration. The abrogation of Treg-cell-mediated suppression could also be demonstrated in a Balb/c (H-2K) to B6/Rag-2KO (H-2K) skin-allograft model. CONCLUSIONS: The blockade of the PD-1/PD-L1 pathway abrogates Treg-mediated immunoregulation, thus suggesting that the PD-1/PD-L1 pathway is required for Treg suppression of the alloreactive responses of CD4+CD25-T cells. This finding has important implications for clarifying the mechanisms of allograft rejection and GvHD.     

Intraoperative blood salvage during liver resection: a randomized controlled trial

OBJECTIVE: A randomized controlled trial was conducted to clarify the effectiveness of intraoperative blood salvage in reducing blood loss. BACKGROUND: Although reduction of central venous pressure (CVP) is thought to decrease blood loss during liver resection, no consistently effective and safe method for obtaining the desired reduction of CVP has been established. METHODS: Living liver donors scheduled to undergo liver graft procurement were randomly assigned to a blood salvage group, in which a blood volume equal to approximately 0.7% of the patient's body weight was collected before the liver transection, or a control group. The surgeons were blinded to the randomization results. The primary outcome measure was blood loss during liver parenchymal division. A multivariate analysis was also performed. RESULTS: Seventy-nine donors were allocated intraoperatively to the blood salvage group (n = 40) or the control group (n = 39). The amount of blood loss during liver transection was significantly smaller in the blood salvage group than in the control group (median loss during transection, 140 mL vs. 230 mL, P = 0.034). The CVP at the beginning of the liver parenchymal division was significantly lower in the blood salvage group than in the control group (median, 5 cm H2O vs. 6 cm H2O, P = 0.005). The results of a multivariate analysis revealed that intraoperative blood salvage offered the advantage of reduced blood loss during liver parenchymal division (adjusted OR, 0.31; 95% CI, 0.11-0.85, P = 0.025). CONCLUSION: Modest intraoperative blood salvage significantly and safely reduced blood loss during hepatic parenchymal transection.     

Very low but stable glomerular filtration rate after living kidney donation: is the concept of “chronic kidney disease” applicable to kidney donors?

Background  

Renal prognosis and outcome of Japanese kidney donors, who have lower preoperative glomerular filtration rate (GFR) and are generally older than their counterparts abroad, have scarcely been investigated. Here, the longitudinal changes in renal function of Japanese kidney donors were studied to clarify the prevalence and consequences of low GFR.     

Prognosis of Japanese Metastatic Renal Cell Carcinoma Patients in the Cytokine Era: A Cooperative Group Report of 1463 Patients

Background

Incidence rate of renal cell carcinoma (RCC) differs among countries. The rates of Asian countries are lower than those of countries in North America or Europe but are exceptionally high in Japanese males. Approximately 30% of patients with RCC have metastasis at initial diagnosis, and another 30% have metastasis after nephrectomy. Clinical studies of risk factors in patients with metastatic RCC (mRCC) are mainly based on data from non-Asian patients.

Objectives

We aimed to investigate the prognosis of Japanese patients and their prognostic factors.

Design, setting, and participants

The subjects of this study were 1463 patients who were clinically diagnosed with RCC with metastasis in 40 Japanese hospitals between January 1988 and November 2002.

Measurements

The primary end point was overall survival calculated from first diagnosis of mRCC to death or last follow-up. We also investigated the relationship between survival and clinical features.

Results and limitations

The median overall survival time was 21.4 mo. The estimated survival rates at 1, 3, 5, and 10 yr were 64.2%, 35.2%, 22.5%, and 9.1%, respectively; they contrasted with data from the United States of 54%, 19%, 10%, and 6%, respectively for the same periods. A high percentage of patients had undergone nephrectomy (80.5%) and metastasectomy (20.8%), both of which were shown to prolong survival.

Conclusions

The median survival time in the present study was approximately twice as long as that of previous studies from North America or Europe. Early diagnosis of metastasis, nephrectomy, metastasectomy, and cytokine-based therapy seemed to improve the prognosis of RCC patients in the present study.     

Risk Factor Analysis of Facet Fusion Following Cervical Lateral Mass Screw Fixation with a Minimum 1-Year Follow-up: Assessment of Maximal Insertional Screw Torque and Incidence of Loosening

Posterior stabilization is a common surgical procedure, which aims for rigid stabilization by facet fusion. Facet non-union has a potential risk of the screw loosening and malalignment. Although some authors have reported the influencing factors about screw loosening in the lumbar spine, there are few reports about the risk factor contributing to the facet non-union in the cervical spine. In all, 22 patients (78 facets and 122 screws) with degenerative cervical kyphosis or spondylolisthesis who underwent decompression and lateral mass screw (LMS) fixation were analyzed. Age, gender, smoking, bone mineral density (BMD), the degree of facet decortication with bone packing, and screw loosening were investigated as risk factors contributing to the facet non-union at each segmental fused level. Facet fusion rate was 85.9% (67/78 facets) and the incidence of loosening was 4.9% (6/122 screws, 4 patients). Insufficient facet decortication with bone packing is a significant risk factor of facet non-union (p <0.05, odds ratio: 26.5). All six loosened screws were associated with bony non-union of the facet and were located in the uppermost or lowermost vertebrae. Comparing loosened screws and stable screws, the average maximal insertional screw torque (MIT) was 9.8 cNm and 39.5 cNm, respectively (p <0.05). Additionally, the length of the stable screws was significantly longer versus the loosened screws (p <0.05). Lower MIT and shorter screw length located near the ends of the lateral mass may predict loosening, which can lead to facet non-union. Sufficient facet decortication with bone packing is one of the important factors contributing to the facet fusion.     

Effects of stress‐shielding on the dynamic viscoelasticity and ordering of the collagen fibers in rabbit Achilles tendon

We investigated the effects of stress‐shielding on both viscoelastic properties and microstructure of collagen fibers in the Achilles tendon by proton double‐quantum filtered (¹H‐DQF) NMR spectroscopy. The right hind‐limbs of 20 Japanese white rabbits were immobilized for 4 weeks in a cast with the ankle in plantarflexion. Dynamic viscoelasticity of the Achilles tendons was measured using a viscoelastic spectrometer. Proton DQF NMR signals were analyzed to determine the residual dipolar coupling of bound water molecules in the Achilles tendons. Both the dynamic storage modulus (E′) and dynamic loss modulus (E″) decreased significantly in the Achilles tendons of the stress‐shielding group. The results of the ¹H‐DQF NMR examination demonstrated significantly reduced residual dipolar coupling in the Achilles tendons of this same group. The disorientation of collagen fibers by stress‐shielding should contribute to degradation of the dynamic storage and loss moduli. The alterations of the collagen fiber orientation that contributed to the function of tendinous tissue can be evaluated by performing an analysis of ¹H DQF NMR spectroscopy. © 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31:1708–1712, 2013     

The effect of human SOD on the survival rate in rats with temporary splanchnic ischemia

The accumulation of oxygen free radicals is reported to occur in the organs subjected to temporary ischemia followed by reperfusion, resulting in the fatal outcome of the animals. The effects of human SOD, a representative scavenger of oxygen free radicals, on the survival rates were investigated in the rats with temporary splanchnic ischemia. The temporary ischemia was induced by the occlusion of anterior mesenteric and celiac arteries for 30min under anesthesia. Prior and after treatment with 2mg/100g of human SOD, iv or sc, produced significant improvements in survival rates. Human SOD, cloned from human placenta DNA and expressed in microorganisms, has extreme homogeneity. The results suggest the possible introduction of human SOD into clinical field as an effective scavenger of oxygen free radicals.(Ogawa R, Bitoh H, Ohi Y: The effect of human SOD on the survival rate in rats with temporary splanchnic ischemia. J Anesth 2: 41–45, 1988)