Showing papers by "Anil Chandraker published in 2011"
TL;DR: Data demonstrate that the PD-L1:B7-1 pathway inhibits potentially pathogenic self-reactive effector CD4+ and CD8+ T cell responses in vivo, and suggest that the immunoinhibitory functions of this pathway may be particularly important during the later phases of diabetogenesis.
Abstract: Programmed death-1 ligand 1 (PD-L1) is a coinhibitory molecule that negatively regulates multiple tolerance checkpoints. In the NOD mouse model, PD-L1 regulates the development of diabetes. PD-L1 has two binding partners, programmed death-1 and B7-1, but the significance of the PD-L1:B7-1 interaction in regulating self-reactive T cell responses is not yet clear. To investigate this issue in NOD mice, we have compared the effects of two anti-PD-L1 Abs that have different blocking activities. Anti-PD-L1 mAb 10F.2H11 sterically and functionally blocks only PD-L1:B7-1 interactions, whereas anti-PD-L1 mAb 10F.9G2 blocks both PD-L1:B7-1 and PD-L1:programmed death-1 interactions. Both Abs had potent, yet distinct effects in accelerating diabetes in NOD mice: the single-blocker 10F.2H11 mAb was more effective at precipitating diabetes in older (13-wk-old) than in younger (6- to 7-wk-old) mice, whereas the dual-blocker 10F.9G2 mAb rapidly induced diabetes in NOD mice of both ages. Similarly, 10F.2H11 accelerated diabetes in recipients of T cells from diabetic, but not prediabetic mice, whereas 10F.9G2 was effective in both settings. Both anti-PD-L1 mAbs precipitated diabetes in adoptive transfer models of CD4(+) and CD8(+) T cell-driven diabetes. Taken together, these data demonstrate that the PD-L1:B7-1 pathway inhibits potentially pathogenic self-reactive effector CD4(+) and CD8(+) T cell responses in vivo, and suggest that the immunoinhibitory functions of this pathway may be particularly important during the later phases of diabetogenesis.
174 citations
TL;DR: Functional data indicate that PDL1 interaction with B7.1 plays an important role in the inhibition of alloimmune responses in vivo and suggests a dominant direction for PDL 1 and B 7.1 interaction.
Abstract: The programmed death ligand 1 (PDL1)/programmed death 1 (PD1) costimulatory pathway plays an important role in the inhibition of alloimmune responses as well as in the induction and maintenance of peripheral tolerance. It has been demonstrated recently that PDL1 also can bind B7.1 to inhibit T cell responses in vitro. Using the bm12 into B6 heart transplant model, we investigated the functional significance of this interaction in alloimmune responses in vivo. PD1 blockade unlike PDL1 blockade failed to accelerate bm12 allograft rejection, suggesting a role for an additional binding partner for PDL1 other than PD1 in transplant rejection. PDL1 blockade was able to accelerate allograft rejection in B7.2-deficient recipients but not B7.1-deficient recipients, indicating that PDL1 interaction with B7.1 was important in inhibiting rejection. Administration of the novel 2H11 anti-PDL1 mAb, which only blocks the PDL1-B7.1 interaction, aggravated chronic injury of bm12 allografts in B6 recipients. Aggravated chronic injury was associated with an increased frequency of alloreactive IFN-γ-, IL-4-, and IL-6-producing splenocytes and a decreased percentage of regulatory T cells in the recipients. Using an in vitro cell culture assay, blockade of the interaction of PDL1 on dendritic cells with B7.1 on T cells increased IFN-γ production from alloreactive CD4(+) T cells, whereas blockade of dendritic cell B7.1 interaction with T cell PDL1 did not. These data indicate that PDL1 interaction with B7.1 plays an important role in the inhibition of alloimmune responses in vivo and suggests a dominant direction for PDL1 and B7.1 interaction.
126 citations
TL;DR: It is demonstrated that PDL1 expression mainly on donor endothelium is functionally important in a fully allogeneic mismatched model for the induction of cardiac allograft tolerance.
58 citations
TL;DR: To the knowledge, these data demonstrate for the first time an important role of Delta1 in alloimmunity, identifying Delta1 ligand as a potential novel target for immunomodulation in transplantation.
Abstract: The Notch signaling pathway has been recently shown to contribute to T cell differentiation in vitro. However, the in vivo function of Notch signaling in transplantation remains unknown. In this study, we investigated the importance of Delta1 in regulating the alloimmune response in vivo. Delta1 expression was upregulated on dendritic cells and monocytes/macrophages upon transplantation in a BALB/c into B6 vascularized cardiac transplant model. Whereas administration of anti-Delta1 mAb only slightly delayed survival of cardiac allografts in this fully MHC-mismatched model, it significantly prolonged graft survival in combination with single-dose CTLA4-Ig or in CD28 knockout recipients. The prolongation of allograft survival was associated with Th2 polarization and a decrease in Th1 and granzyme B-producing cytotoxic T cells. The survival benefit of Delta1 blockade was abrogated after IL-4 neutralization and in STAT6KO recipients, but was maintained in STAT4KO recipients, reinforcing the key role of Th2 cell development in its graft-prolonging effects. To our knowledge, these data demonstrate for the first time an important role of Delta1 in alloimmunity, identifying Delta1 ligand as a potential novel target for immunomodulation in transplantation.
40 citations
TL;DR: It is suggested that in vivo–activated monocytes in peripheral blood spontaneously secrete proinflammatory cytokines in renal allograft recipients with transplant glomerulopathy and seem to be under the regulation of functional regulatory T cells in this setting.
Abstract: Background. Although there is ample evidence about the role of adaptive immunity in the development of chroni allograft dysfunction, little is known about the contribution of innate immunity to this process. Herein, we studied th relationship between inflammation, chronic biopsy scores, and anti-human leukocyte antigen (HLA) circulating a] loantibodies in a cohort of 57 patients recruited at our center. Methods. Available biopsies (n=27) were graded for chronic lesion scores according to Banff criteria. The production on cytokines by peripheral blood mononuclear cells after 48 hr of culture under resting conditions was quantified by Lumineux Tumor necrosis factor (TNF)-α secretion assay and depletion studies were used to identify the source of these cytokines. Results. There was a high correlation between the levels of interleukin (IL)-1β, IL-6, and TNF-α (r>0.8, P<0.001 fo all correlations). The levels of these cytokines were associated with transplant glomerulopathy (IL-1β, P=0.019; IL-6 P=0.015; and TNF-α, P=0.006) but not with other chronic lesions or anti-HLA circulating alloantibodies. TNF-α wa predominantly secreted by monocytes (percent of TNF-α secreting cells: 20.4 ±4.8 vs. 1.2±0.5 vs. 1.4±0.6 vs. 1.7±0. for CD14 + , CD4 + , CD8 + , and CD19 + cells, respectively; all P<0.01 vs. CD14 + ). The levels of all three proinflamma tory cytokines were significantly reduced after monocyte depletion. Intriguingly, cytokine levels increased after ex viv depletion of regulatory T cells (all P<0.001). Conclusions. Taken together, these data suggest that in vivo―activated monocytes in peripheral blood spontaneousl secrete proinflammatory cytokines in renal allograft recipients with transplant glomerulopathy and seem to be unde the regulation of functional regulatory T cells in this setting.
32 citations
TL;DR: Enhancing the operational role of naturally occurring donor-specific Tregs in allograft recipients by adjusting the immunosuppression protocol may be advantageous particularly for patients with ongoing chronic rejection.
21 citations
TL;DR: A case of a 70-year-old highly sensitized woman with end-stage renal disease caused by diabetic nephropathy who underwent deceased donor kidney transplant who was noted to have hypophosphatemia with undetectable serum phosphate levels, and she reported mild diarrhea.
20 citations
TL;DR: The safety and efficacy of rabbit antithymocyte globulin (r‐ATG) with basiliximab in renal transplant recipients for whom an early steroid withdrawal (ESW) regimen was planned is compared.
Abstract: Study Objective. To compare the safety and efficacy of rabbit antithymocyte globulin (r-ATG) with basiliximab in renal transplant recipients for whom an early steroid withdrawal (ESW) regimen was planned.
Design. Single-center, retrospective, cohort study.
Setting. Tertiary care medical center, including inpatient hospital stays and outpatient nephrology clinics.
Patients. Ninety-nine consecutive adult recipients of living- or deceased-donor renal transplants between January 1, 2004, and December 31, 2007, in whom ESW was planned and who received either r-ATG or basiliximab; patients receiving an extended-criteria kidney donation or a donation after cardiac death were excluded.
Measurements and Main Results. All patients received mycophenolate mofetil and tacrolimus as maintenance therapy with planned ESW. Induction therapy was either r-ATG 1.5 mg/kg/day for 4 days (68 patients) or basiliximab 20 mg on postoperative days 0 and 4 (31 patients). The primary composite end point of biopsy-proven acute rejection (BPAR), graft loss, and death occurred in 6 patients (9%) and 9 patients (29%) in the r-ATG and basiliximab groups at 1 year after transplantation, respectively (p=0.01), with rates of 7% (5/68 patients) and 26% (8/31 patients) for BPAR (p=0.02), 0% and 3% (1/31 patients) for graft loss (p=0.31), and 2% (1/68 patients) and 0% for patient death (p>0.99). Average time to first BPAR was significantly longer in the r-ATG group (mean ± SD 151.4 ± 82.9 vs 53.6 ± 68.4 days, p<0.01). Kidney function at 12 months was similar between the two groups.
Conclusion. Rabbit-ATG was associated with a lower frequency and delayed onset of BPAR compared with basiliximab in renal transplant recipients who received an ESW regimen.
18 citations
TL;DR: Urine cytology (including ureteral wash cytology) may be used as a reliable diagnostic tool in patients with 1 or more risk factors for development of TCC and might be an option in patients at high risk of developing TCC.
17 citations
TL;DR: Living kidney donors are donating at more advanced ages, and the majority are overweight or obese in recent years, which means the majority of living donor–recipient pairs have BMI mismatch, and extreme BMI mismatch where the living donor is heavier may confer an independent risk for allograft loss.
Abstract: Background and objectives
Age and body mass index (BMI) of kidney donors and recipients affect kidney allograft outcomes. Moreover, while deceased donor and recipient body size mismatch have been reported to influence allograft outcomes, how BMI mismatch in living kidney donor–recipient pairs affect graft survival is not well defined.
13 citations
TL;DR: It was found that renal transplant outcome and patient survival were not adversely affected by the presence of accidently discovered RCC at the time of transplantation, and patients seem to be at significantly higher risk of the occurrence of RCC in the remaining native kidney.
Abstract: BACKGROUND Renal tumors are common in the pretransplant end-stage renal disease population. Their impact on transplant outcome has not been well addressed. METHODS This study is a retrospective follow-up observational study conducted in 258 renal transplant recipients. All patients had an ipsilateral native nephrectomy at the time of transplantation. We reviewed the histopathology of all native nephrectomies to gauge the prevalence of renal cell carcinoma (RCC) and to investigate the impact of accidental discovery of RCC on graft and patient outcome. RESULTS RCC was found in 12 patients (4.7%): clear type in 9 patients, and chromophobe and combined clear and papillary type in 1 and 2 patients, respectively. There was no significant difference in human leukocyte antigen mismatch, primary immunosuppression, occurrence of rejection, graft function, and patient and graft survival between patients with or without RCC. RCC presented in the other native kidney in three patients (25%) posttransplantation and one of them developed metastasis 4 years after renal transplantation in the RCC group in comparison with eight patients in the control group (3.3%; P<0.001). The median follow-up period was 56 months for the RCC group and 65 months for the control group. CONCLUSIONS We found that renal transplant outcome and patient survival were not adversely affected by the presence of accidently discovered RCC at the time of transplantation. These patients seem to be at significantly higher risk of the occurrence of RCC in the remaining native kidney. Further studies are warranted to confirm our results.
TL;DR: These 2 cases are the first to demonstrate that IL-2RAs can be used as an alternative to a CNI in a de novo immunosuppressive regimen, and this is the first report to illustrate successful long-term use of IL- 2RAS in renal transplant recipients.
Abstract: Objective:To report what we believe to be the first 2 cases of long-term (>24 months) intermittent intravenous interleukin-2 receptor antibody (IL-2RA) therapy for maintenance immunosuppression fol...
TL;DR: The side-effect profile of belatacept has been shown to be similar or improved compared with CNI therapy; however, the risk of malignancy, specifically post-transplant lymphoproliferative disorder is notably higher.
Abstract: Belatacept (LEA29Y) is an intravenous biologic for long-term maintenance immunosuppressive therapy in renal transplant recipients. It is currently being reviewed by the United States Food and Drug Administration (FDA) as a prophylactic therapy against acute cellular rejection (ACR) in de novo renal transplant recipients. To provide an in-depth review of the pharmacology, clinical efficacy, safety, and applications of belatacept, a MEDLINE database search was performed for all English-language articles evaluating the pharmacology and efficacy of belatacept, as well as abstracts from recent scientific meetings. Belatacept is a potent inhibitor of B7 binding to CD28, a potent T-cell co-stimulatory signal. The B7 ligands are found on the surface of antigen-presenting cells, specifically B7-1 (CD80) and B7-2 (CD86). CD80 and CD86 are essential ligands for CD28, a critical component of costimulation in the three-signal transplant model of T-cell activation. Belatacept has proven noninferiority compared with calcineurin-inhibitor (CNI)-based regimens in the incidence of patient and allograft survival. However, the incidence and severity of ACR has been shown to be increased in patients receiving belatacept therapy. Although rates of ACR are increased in patients receiving belata- cept, an overall improvement in allograft function has been described with average improve- ments in glomerular filtration rates of up to 12-15 mL/min higher than CNI-based regimens. The side-effect profile of belatacept has been shown to be similar or improved compared with CNI therapy; however, the risk of malignancy, specifically post-transplant lymphoproliferative disorder is notably higher. Because of the marked increase in the risk of malignancy and ACR, approval of belatacept by the FDA will rely on more robust data from long-term follow-up of currently available data.