Marker Based In-vitro Antioxidant Potential,Microscopy and Validated High Performance Thin Layer Chromatographic Method for Saffron

Proceedings of the National Academy of Sciences, India Section B: Biological Sciences - In vitro antioxidant potential of methanolic extract of saffron and crocetin was assessed along with...     

Pathogen Stimulation History Impacts Donor‐Specific CD8+ T Cell Susceptibility to Costimulation/Integrin Blockade–Based Therapy

Recent studies have shown that the quantity of donor‐reactive memory T cells is an important factor in determining the relative heterologous immunity barrier posed during transplantation. Here, we hypothesized that the quality of T cell memory also potently influences the response to costimulation blockade‐based immunosuppression. Using a murine skin graft model of CD8⁺ memory T cell–mediated costimulation blockade resistance, we elicited donor‐reactive memory T cells using three distinct types of pathogen infections. Strikingly, we observed differential efficacy of a costimulation and integrin blockade regimen based on the type of pathogen used to elicit the donor‐reactive memory T cell response. Intriguingly, the most immunosuppression‐sensitive memory T cell populations were composed primarily of central memory cells that possessed greater recall potential, exhibited a less differentiated phenotype, and contained more multi‐cytokine producers. These data, therefore, demonstrate that the memory T cell barrier is dependent on the specific type of pathogen infection via which the donor‐reactive memory T cells are elicited, and suggest that the immune stimulation history of a given transplant patient may profoundly influence the relative barrier posed by heterologous immunity during transplantation.     

Rapamycin ameliorates the CTLA4‐Ig–mediated defect in CD8+ T cell immunity during gammaherpesvirus infection

Latent viral infections are a major concern among immunosuppressed transplant patients. During clinical trials with belatacept, a CTLA4‐Ig fusion protein, patients showed an increased risk of Epstein–Barr virus‐associated posttransplant lymphoproliferative disorder, thought to be due to a deficient primary CD8⁺ T cell response to the virus. Using a murine model of latent viral infection, we observed that rapamycin treatment alone led to a significant increase in virus‐specific CD8⁺ T cells, as well as increased functionality of these cells, including the ability to make multiple cytokines, while CTLA4‐Ig treatment alone significantly dampened the response and inhibited the generation of polyfunctional antigen‐specific CD8⁺ T cells. However, the addition of rapamycin to the CTLA4‐Ig regimen was able to quantitatively and qualitatively restore the antigen‐specific CD8⁺ T cell response to the virus. This improvement was physiologically relevant, in that CTLA4‐Ig treated animals exhibited a greater viral burden following infection that was reduced to levels observed in untreated immunocompetent animals by the addition of rapamycin. These results reveal that modulation of T cell differentiation though inhibition of mTOR signaling can restore virus‐specific immune competence even in the absence of CD28 costimulation, and have implications for improving protective immunity in transplant recipients.     

Relationships Between Eight Measures of Suspect Effort

Previous studies have recommended that multiple measures be employed concurrently to provide converging evidence regarding the presence of suspect effort during neuropsychological assessment. However, if the tests are highly correlated they do not represent independent sources of information. To date, no study has examined correspondence between effort tests. The present study assessed the relationships between eight measures which can be used to assess effort (Rey 15-item, Rey Dot Counting Test, Rey Word Recognition Test, RAVLT recognition trial, Rey-Osterrieth Complex Figure Test effort equation, Digit Span, Warrington Recognition Memory Test-Words, and “b” Test) in a sample of 105 patients in litigation or attempting to obtain/maintain disability compensation and who displayed noncredible symptoms based on psychometric performance and behavioral criteria. Modest to moderate correlations were observed between test summary scores with only two measures sharing more than 50% score variance (Digit Span and Dot Counting). Moderate correlations were also observed between individual test scores reflecting indices of response time, free recall, recognition, and false positive errors, providing possible evidence that patients may use specific strategies when producing noncredible performances. Overall the results suggest that the use of these various tests generally provides nonredundant data regarding patient credibility in neuropsychological evaluations.     

Liver Transplantation Outcome in Patients With Angiographically Proven Coronary Artery Disease: A Multi‐Institutional Study

Over the last decade the age of liver transplant (LT) recipients and the likelihood of coronary artery disease (CAD) in this population have increased. There are no multicenter studies that have examined the impact of CAD on LT outcomes. In this historical cohort study, we identified adult LT recipients who underwent angiography prior to transplantation at seven institutions over a 12‐year period. For each patient we recorded demographic data, recipient and donor risk factors, duration of follow‐up, the presence of angiographically proven obstructive CAD (≥50% stenosis) and post‐LT survival. Obstructive CAD was present in 151 of 630 patients, the CAD(+) group. Nonobstructive CAD was found in 479 patients, the CAD(?) group. Patient survival was similar for the CAD(+) group (adjusted HR 1.13, CI = [0.79, 1.62], p = 0.493) compared to the CAD(?) group. The CAD(+) patients were further stratified into severe (CADsev, >70% stenosis, n = 96), and moderate CAD (CADmod, 50–70% stenosis, n = 55) groups. Survival for the CADsev (adjusted HR = 1.26, CI = [0.83, 1.91], p = 0.277) and CADmod (adjusted HR = 0.93, CI = [0.52, 1.66], p = 0.797) groups were similar to the CAD(?) group. We conclude that when current CAD treatment strategies are employed prior to transplant, post‐LT survival is not significantly different between patients with and without obstructive CAD.     

Predictors of nadir serum creatinine after drainage of bilaterally obstructed kidneys due to different etiologies

International Urology and Nephrology - To identify the predictors of nadir serum creatinine (SCr) after drainage of bilaterally obstructed kidneys (BOKs) by different modes: double-J stent (JJ)...     

Memory T cell–mediated rejection is mitigated by FcγRIIB expression on CD8+ T cells

Donor‐reactive memory T cells generated via heterologous immunity represent a potent barrier to long‐term graft survival following transplantation because of their increased precursor frequency, rapid effector function, altered trafficking patterns, and reduced reliance on costimulation signals for activation. Thus, the identification of pathways that control memory T cell survival and secondary recall potential may provide new opportunities for therapeutic intervention. Here, we discovered that donor‐specific effector/memory CD8⁺ T cell populations generated via exposure to acute vs latent vs chronic infections contain differential frequencies of CD8⁺ T cells expressing the inhibitory Fc receptor FcγRIIB. Results indicated that frequencies of FcγRIIB‐expressing CD8⁺ donor‐reactive memory T cells inversely correlated with allograft rejection. Furthermore, adoptive T cell transfer of Fcgr2b^?/? CD8⁺ T cells resulted in an accumulation of donor‐specific CD8⁺ memory T cells and enhanced recall responses, indicating that FcγRIIB functions intrinsically to limit T cell CD8⁺ survival in vivo. Lastly, we show that deletion of FcγRIIB on donor‐specific CD8⁺ memory T cells precipitated costimulation blockade‐resistant rejection. These data therefore identify a novel cell‐intrinsic inhibitory pathway that functions to limit the risk of memory T cell–mediated rejection following transplantation and suggest that therapeutic manipulation of this pathway could improve outcomes in sensitized patients.     

Triple (GGTA1, CMAH,B2M) modified pigs expressing an SLA class Ilow phenotype—Effects on immune status and susceptibility to human immune responses

Porcine xenografts lacking swine leukocyte antigen (SLA) class I are thought to be protected from human T cell responses. We have previously shown that SLA class I deficiency can be achieved in pigs by CRISPR/Cas9‐mediated deletion of β₂‐microglobulin (B2M). Here, we characterized another line of genetically modified pigs in which targeting of the B2M locus did not result in complete absence of B2M and SLA class I but rather in significantly reduced expression levels of both molecules. Residual SLA class I was functionally inert, because no proper differentiation of the CD8⁺ T cell subset was observed in B2M^low pigs. Cells from B2M^low pigs were less capable in triggering proliferation of human peripheral blood mononuclear cells in vitro, which was mainly due to the nonresponsiveness of CD8⁺ T cells. Nevertheless, cytotoxic effector cells developing from unaffected cell populations (eg, CD4⁺ T cells, natural killer cells) lysed targets from both SLA class I⁺ wildtype and SLA class I^low pigs with similar efficiency. These data indicate that the absence of SLA class I is an effective approach to prevent the activation of human CD8⁺ T cells during the induction phase of an anti‐xenograft response. However, cytotoxic activity of cells during the effector phase cannot be controlled by this approach.     

Hepatopulmonary syndrome associated with nodular regenerative hyperplasia after liver transplantation in a child

HPS is a significant complication of portal hypertension in children with chronic liver disease and is an established indication for LT. It is characterized clinically by the triad of pulmonary vascular dilatation causing hypoxemia in the setting of advanced liver disease. NRH, a cause of non‐cirrhotic portal hypertension, is characterized by diffuse benign transformation of the hepatic parenchyma into small regenerative nodules with minimal or no fibrosis. Development of NRH and HPS in pediatric LT recipients has not been reported, although occasional cases have been reported in adult LT recipients. In this report, we discuss a case of a three‐yr‐old male who developed HPS, two yr after LT. Pulmonary and cardiac causes for hypoxemia were ruled out by appropriate investigations including a chest X ray, echocardiogram, cardiac catheterization, and a CT angiographic study. The diagnosis of HPS was confirmed via bubble echocardiogram that demonstrated intrapulmonary shunting. Open liver biopsy revealed marked NRH. The patient underwent liver retransplantation that resulted in complete reversal of his pulmonary symptoms and normal oxygen saturations within three months after LT.