Broad T cell depletion has been used as an integral part of treatment in transplantation and autoimmune diseases. Following depletion, residual T cells undergo homeostatic proliferation and convert to memory-like T cells. In this study, we investigated the effect of T cell depletion by antilymphocyte serum (ALS), a polyclonal anti-T cell Ab, on CD4+ regulatory T cells. After ALS treatment, CD4+CD25+ T cells underwent proliferation and expressed a memory T cell marker, CD44. One week after ALS treatment, both CD25+ and CD25− T cells exhibited increased suppression of alloresponses in vitro, which waned thereafter to the levels mediated by naive CD25+ and CD25− T cells. By real-time PCR analyses, ALS treatment of CD4-deficient mice adoptively transferred with Thy1.2+CD4+CD25+Foxp3+ and Thy1.1+CD4+CD25−Foxp3− T cells resulted in the appearance of Thy1.2+CD4+CD25−Foxp3+ and Thy1.1+CD4+CD25+Foxp3+ T cells, suggesting the conversion between CD25+ and CD25− T cells. Naive CD25+ T cells expressed a higher level of intracellular Bcl-xL than CD25− T cells. Up-regulation of the Bcl-xL molecule during ALS-induced homeostatic expansion further promoted survival of CD25+ and, to a lessor degree, CD25− cells. These results indicate that CD25+ T cells are spared from ALS-mediated deletion, with some CD25+ T cells converting to CD25− T cells, and continue to exhibit regulatory activity. The concomitant presence of T cell deletion and continuous regulatory T cell activity may underlie the therapeutic effect of ALS, particularly in treatment of autoimmune diseases.

T cell depletion is a widely used approach in clinical transplantation. However, not all T cells are equally sensitive to depletion therapies and a significant fraction of T cells persists even after aggressive treatment. The functional attributes of such T cells and the mechanisms responsible for their resistance to depletion are poorly studied. In the present study, we showed that CD4+ T cells that are resistant to polyclonal anti-lymphocyte serum (ALS) mediated depletion exhibit phenotypic features of memory cells and uniformly express OX40 on the cell surface. Studies using the foxp3gfp knockin mice revealed that the remaining CD4+OX40+ cells consist of Foxp3+ Tregs and Foxp3− T effector/memory cells. The ALS-resistant CD4+OX40+ cells failed to mediate skin allograft rejection upon adoptive transferring into congenic Rag−/− mice, but removal of Foxp3+ Tregs from the OX40+ cells resulted in prompt skin allograft rejection. Importantly, OX40 is critical to survival of both Foxp3+ Tregs and T effector/memory cells. However, OX40 exhibits opposing effects on the functional status of Foxp3+ Tregs and T effector/memory cells, as stimulation of OX40 on T effector cells induced amplified cell proliferation but stimulation of OX40 on the Foxp3+ Tregs impaired their suppressor functions. Our study demonstrates that OX40 is a critical molecule in regulating survival and functions of depletion-resistant T cells; and these findings may have important clinical implications.

Background:In Asians, the risk of irinotecan-induced severe toxicities is related in part to UGT1A1*6 (UGT, UDP glucuronosyltransferase) and UGT1A1*28, variant alleles that reduce the elimination of SN-38, the active metabolite of irinotecan. We prospectively studied the relation between the UGT1A1 genotype and the safety of irinotecan-based regimens in Japanese patients with advanced colorectal cancer, and then constructed a nomogram for predicting the risk of severe neutropenia in the first treatment cycle.Methods:Safety data were obtained from 1312 patients monitored during the first 3 cycles of irinotecan-based regimen in a prospective observational study. In development of the nomogram, multivariable logistic regression analysis was used to test the associations of candidate factors to severe neutropenia in the first cycle. The final nomogram based on the results of multivariable analysis was constructed and validated internally using a bootstrapping technique and externally in an independent data set (n=350).Results:The UGT1A1 genotype was confirmed to be associated with increased risks of irinotecan-induced grade 3 or 4 neutropenia and diarrhoea. The final nomogram included type of regimen, administered dose of irinotecan, gender, age, UGT1A1 genotype, Eastern Cooperative Oncology Group performance status, pre-treatment absolute neutrophil count, and total bilirubin level. The model was validated both internally (bootstrap-adjusted concordance index, 0.69) and externally (concordance index, 0.70).Conclusions:Our nomogram can be used before treatment to accurately predict the probability of irinotecan-induced severe neutropenia in the first cycle of therapy. Additional studies should evaluate the effect of nomogram-guided dosing on efficacy in patients receiving irinotecan.

Background— Cardioplegia and cardiopulmonary bypass (CP/CPB) leads to an increase in circulating progenitor cells. The role of stromal-derived factor-1α (SDF-1α), a key regulator of progenitor cell mobilization, and other cytokines in this process is not clear. Methods and Results— Peripheral blood (n=24), atrial and skeletal tissue (n=6) samples were taken from patients undergoing CP/CPB before (pre-CP/CPB), 4 hours (post-CP/CPB), and 4 days (POD4) after CP/CPB. The number of circulating CD34+CXCR4+ cells increased post-CP/CPB (442±53 versus 286±27; P =0.04 versus pre-CP/CPB), but not at POD4 (382±50; P =0.28 versus pre-CP/CPB). Plasma levels of SDF-1α increased post-CP/CPB as compared with pre-CP/CPB (3325±325 versus 2911±165 pg/mL; P =0.046) but returned to baseline at POD4 (2838±224 pg/mL; P =0.90). Plasma levels of vascular endothelial growth factor were similar post-CP/CPB ( P =0.90 versus pre-CP/CPB) but increased at POD4 (220±40 pg/mL versus 134±26 pg/mL; P =0.04 versus pre-CP/CPB). Serum levels of granulocyte-colony stimulating factor (G-CSF) increased early after CP/CPB as compared with pre-CP/CPB (265.0±41.7 versus 11.1±1.1 pg/mL; P <0.001) and returned to baseline at POD4 ( P =0.84 versus pre-CP/CPB). The circulating CD34+CXCR4+ cells were positively correlated with plasma levels of SDF-1α early after CP/CPB ( r =0.56, P <0.01), but not at other times. Protein expression of SDF-1α was elevated in the atrial myocardium after CP/CPB (9.4-fold; P =0.03). Conclusions— Exposure to CP/CPB leads to an increase in circulating CD34+CXCR4+ progenitor cells, which is associated with increased myocardial SDF-1α expression. The numbers of CD34+CXCR4+ progenitor cells positively correlate with the plasma levels of SDF-1α post-CP/CPB, suggesting an important role of SDF-1α in progenitor cell mobilization.

Alloreactive memory T cells mediate accelerated rejection. We investigated the effect of polyclonal anti-T-cell antibody (ALS

Management of patients undergoing dialysis after inguinal hernia surgery has not been standardized. This report presents the results of 9 patients with inguinal hernias (11 hernias) who were undergoing continuous ambulatory peritoneal dialysis (CAPD). All patients treated in this hospital since 2007 have returned to CAPD within 3 days after surgery without switching to hemodialysis (HD). The mean durations for resuming CAPD after surgery were 7.6 days from 1998 through 2007 and 2.3 days since 2008. The surgical procedure was performed with a polypropylene mesh in all cases. Local anesthesia was utilized for one patient with low cardiac function. All patients recovered rapidly, with no uremia or dialysis-related complications. No leakage or hernia recurrence was observed over the subsequent observation period (56.2 months). This experience suggests the possibility that interim HD can therefore be skipped in patients undergoing CAPD if the hernia sacs are closed tightly. Local anesthesia seems to be safe for high-risk hernia patients undergoing CAPD.

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The Thymoglobulin, SRL, and DBM protocol is simple and produces long-term kidney allograft survival in NHP although additional treatment modalities may be necessary for induction of long-term tolerance.