An Analysis of Lymphocyte Phenotype After Steroid Avoidance With Either Alemtuzumab or Basiliximab Induction in Renal Transplantation

Cherukuri, Aravind; Salama, Alan D.; Carter, C.; Smalle, Natuley; McCurtin, RE; Hewitt, Eric W.; Hernandez-Fuentes, Maria P.; Clark, Brendan; Baker, Richard J.

doi:10.1111/j.1600-6143.2011.03891.x

Cited by 46 publications

(31 citation statements)

References 43 publications

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“…This hypothesis has been further strengthened by another work that showed that a significant expansion of regulatory-type B cells (defined as CD19 + CD5 + CD1d high ) is associated with superior graft function and that this pattern is more common after alemtuzumab induction. 45 However, although this hypothesis is interesting, it has been challenged by recent conflicting reports from two independent groups showing that alemtuzumab-induced B cell depletion/reconstitution is associated with a higher incidence of AMR compared with induction with ATG. 46,47 Basiliximab is a chimeric mousehuman nondepleting mAb targeting the a-chain (CD25) of the IL-2 receptor (Figure 1).…”

Section: Effect Of Induction Therapy On Dndsa Generationmentioning

confidence: 76%

Effect of Immunosuppressive Drugs on Humoral Allosensitization after Kidney Transplant

Thaunat

Koenig

Leibler³

et al. 2016

JASN

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The negative effect of donor-specific antibodies on the success of solid transplant is now clearly established. However, the lack of effective treatment to prevent the development of antibody-mediated lesions deepens the need for clinicians to focus on primary prevention of de novo humoral allosensitization. Among the factors associated with the risk of developing de novo donor-specific antibodies, therapeutic immunosuppression is the most obvious parameter in which improvement is possible. Beyond compliance and the overall depth of immunosuppression, it is likely that the nature of the drugs is also crucial. Here, we provide an overview of the molecular effect of the various immunosuppressive drugs on B cell biology. Clinical data related to the effect of these drugs on de novo humoral allosensitization are also examined, providing a platform from which clinicians can optimize immunosuppression for prevention of de novo donor-specific antibody generation at the individual level.

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Section: Effect Of Induction Therapy On Dndsa Generationmentioning

confidence: 76%

Effect of Immunosuppressive Drugs on Humoral Allosensitization after Kidney Transplant

Thaunat

Koenig

Leibler³

et al. 2016

JASN

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“…Moreover, we recently showed that stable renal transplant patients with superior graft function, irrespective of immunosuppressive regimen, have higher numbers of both total B cells and TrBs compared with those with reduced renal function. 35 In this study, not only are TrBs reduced in the setting of rejection, but their cytokine profile and functional activity upon in vitro noncognate polyclonal stimulation are abnormal. Closer inspection reveals that most of the patients (80%) in the GD-R group exhibited microvascular inflammation and scarring with or without complement (C4d) deposition, and serologic evidence of circulating donor-specific HLA antibody-all features of CAMR.…”

Section: Discussionmentioning

confidence: 98%

Immunologic Human Renal Allograft Injury Associates with an Altered IL-10/TNF-α Expression Ratio in Regulatory B Cells

Cherukuri

Rothstein²,

Clark

et al. 2014

Journal of the American Society of Nephrology

136

132

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Human B cells with immunoregulatory properties in vitro (Bregs) have been defined by the expression of IL-10 and are enriched in various B-cell subsets. However, proinflammatory cytokine expression in B-cell subsets is largely unexplored. We examined the cytokine profiles of human PBMCs and found that subsets of CD24 hi CD38 hi transitional B cells (TrBs), CD24 hi CD27 + memory B cells, and naïve B cells express IL-10 and the proinflammatory cytokine TNF-a simultaneously. TrBs had the highest IL-10/TNF-a ratio and suppressed proinflammatory helper T cell 1 (Th1) cytokine expression by autologous T cells in vitro more potently than memory B cells did, despite similar IL-10 expression. Whereas neutralization of IL-10 significantly inhibited TrB-mediated suppression of autologous Th1 cytokine expression, blocking TNF-a increased the suppressive capacity of both memory and naïve B-cell subsets. Thus, the ratio of IL-10/TNF-a expression, a measure of cytokine polarization, may be a better indicator of regulatory function than IL-10 expression alone. Indeed, compared with TrB cells from patients with stable kidney graft function, TrBs from patients with graft rejection displayed similar IL-10 expression levels but increased TNF-a expression (i.e., reduced IL-10/TNF-a ratio), did not inhibit in vitro expression of Th1 cytokines by T cells, and abnormally suppressed expression of Th2 cytokines. In patients with graft dysfunction, a low IL-10/TNF-a ratio in TrBs associated with poor graft outcomes after 3 years of follow-up. In summary, these results indicate that B cell-mediated immune regulation is best characterized by the cytokine polarization profile, a finding that was confirmed in renal transplant patients.

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“…Another study by Welberry Smith et al (9) using AZ and tacrolimus monotherapy also found lower BPAR relative to basiliximab, tacrolimus, and mycophenolate mofetil (10%/58 versus 24%/58; P=0.05). Cherukuri et al (10) found that AZ resulted in significantly less BPAR compared with basiliximab with both groups having similar tacrolimus levels and mycophenolate mofetil dosage (10.3%/51 versus 24.1%/45, For overall patient survival 13,752 observations out of 14,025 were used in the model. aHR, adjusted hazard ratio; 95% CI, 95% confidence interval; aOR, adjusted odds ratio; ATG, antithymocyte globulin.…”

Section: Discussionmentioning

confidence: 99%

“…Over the last decade, alemtuzumab (AZ) (Campath-1 H) has been used in kidney transplant immunosuppressive protocols at a number of centers (5)(6)(7)(8)(9)(10)(11)(12)(13)(14). Various single and multicenter studies, both randomized and nonrandomized, are reasonably consistent in demonstrating the effectiveness of AZ as an induction or preconditioning agent in renal transplant recipients usually in the context of steroid avoidance or early withdrawal.…”

Section: Introductionmentioning

confidence: 99%

Outcomes Associated with Steroid Avoidance and Alemtuzumab among Kidney Transplant Recipients

Serrano

Friedmann

Ahsanuddin

et al. 2015

Clinical Journal of the American Society of Nephrology

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Background and objectives Alemtuzumab is a humanized anti-CD52 monoclonal antibody used as induction in kidney transplantation (KTX) since 2003. Few studies have evaluated long-term outcomes of this agent or changes in outcomes over time.Design, setting, participants, & measurements A retrospective cohort study was performed examining United States registry data from 2003 to 2014 of primary KTX recipients receiving induction with alemtuzumab (AZ; n=5521) or antithymocyte globulin (ATG; n=8504) and maintenance immunosuppression with tacrolimus and mycophenolate mofetil and early withdrawal of steroids. The primary outcome was overall death-censored graft survival (DCGS), and secondary outcomes were overall patient survival and 1-year acute rejection. Multivariate models were fit with donor, recipient, and transplant covariates. Because poorer outcomes with AZ may occur from a learning curve impact with the use of a new medication, transplant year was categorized into three time periods to evaluate outcomes over time (2003-2005, 2006-2008, $2009), and an interaction term of induction type with transplant year category was included in all models to test for era impacts.Results On multivariate analysis of DCGS there was a significant interaction between AZ and era (P,0.001). Risk-adjusted patient survival (aHR, 1.32; 95% CI, 1.08 to 1.61; aHR, 1.26; 95% CI, 1.09 to 1.46; and aHR, 1.10; 95% CI, 0.93 to 1.29 by era, respectively) and acute rejection (adjusted odds ratio [aOR], 1.17; 95% CI, 0.96 to 1.42; aOR, 0.94; 95% CI, 0.82 to 1.07; aOR, 0.89; 95% CI, 0.81 to 0.98 by era, respectively) with AZ was comparable with ATG in the most recent era; however, there was no significant interaction with time (P=0.13 and P=0.06, respectively).Conclusions Current alemtuzumab utilization is associated with comparable graft and patient survival and acute rejection compared with ATG. Graft survival with alemtuzumab has improved over time.

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An Analysis of Lymphocyte Phenotype After Steroid Avoidance With Either Alemtuzumab or Basiliximab Induction in Renal Transplantation

Cited by 46 publications

References 43 publications

Effect of Immunosuppressive Drugs on Humoral Allosensitization after Kidney Transplant

Effect of Immunosuppressive Drugs on Humoral Allosensitization after Kidney Transplant

Immunologic Human Renal Allograft Injury Associates with an Altered IL-10/TNF-α Expression Ratio in Regulatory B Cells

Outcomes Associated with Steroid Avoidance and Alemtuzumab among Kidney Transplant Recipients

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