I. Raul Badell

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Selective CD28 Blockade Results in Superior Inhibition of Donor-Specific T Follicular Helper Cell and Antibody Responses Relative to CTLA4-Ig

American Journal of Transplantation (2017)

I. Raul Badell G.M. La Muraglia D. Liu Maylene E. Wagener Guoshan Ding

Donor-specific antibodies (DSAs) are a barrier to improved long-term outcomes after kidney transplantation. Costimulation blockade with CTLA4-Ig has shown promise as a potential therapeutic strategy to control DSAs. T follicular helper (Tfh) cells, a subset of CD4+ T cells required for optimal antibody production, are reliant on the CD28 costimulatory pathway. We have previously shown that selective CD28 blockade leads to superior allograft survival through improved control of CD8+ T cells relative to CTLA4-Ig, but the impact of CD28-specific blockade on CD4+ Tfh cells is unknown. Thus, we identified and characterized donor-reactive Tfh cells in a murine skin transplant model and then used this model to evaluate the impact of selective CD28 blockade with an anti-CD28 domain antibody (dAb) on the donor-specific Tfh cell-mediated immune response. We observed that the anti-CD28 dAb led to superior inhibition of donor-reactive CXCR5+ PD-1high Tfh cells, CD95+ GL7+ germinal center B cells and DSA formation compared with CTLA4-Ig. Interestingly, donor-reactive Tfh cells differentially upregulated CTLA4 expression, suggesting an important role for CTLA4 in mediating the superior inhibition observed with the anti-CD28 dAb. Therefore, selective CD28 blockade as a novel approach to control Tfh cell responses and prevent DSA after kidney transplantation warrants further study.

CXCR5

10.1111/ajt.14400

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Citations (36)

Alternative Immunomodulatory Strategies for Xenotransplantation: CD40/154 Pathway-Sparing Regimens Promote Xenograft Survival

American Journal of Transplantation (2012)

Peter Thompson I. Raul Badell M.C. Lowe A Turner J. M. Palomino

Immunosuppressive therapies that block the CD40/CD154 costimulatory pathway have proven to be uniquely effective in preclinical xenotransplant models. Given the challenges facing clinical translation of CD40/CD154 pathway blockade, we examined the efficacy and tolerability of CD40/CD154 pathway-sparing immunomodulatory strategies in a pig-to-nonhuman primate islet xenotransplant model. Rhesus macaques were rendered diabetic with streptozocin and given an intraportal infusion of ∼50 000 islet equivalents/kg wild-type neonatal porcine islets. Base immunosuppression for all recipients included maintenance therapy with belatacept and mycophenolate mofetil plus induction with basiliximab and LFA-1 blockade. Cohort 1 recipients (n = 3) were treated with the base regimen alone; cohort 2 recipients (n = 5) were additionally treated with tacrolimus induction and cohort 3 recipients (n = 5) were treated with alefacept in place of basiliximab, and more intense LFA-1 blockade. Three of five recipients in both cohorts 2 and 3 achieved sustained insulin-independent normoglycemia (median rejection-free survivals 60 and 111 days, respectively), compared to zero of three recipients in cohort 1. These data show that CD40/CD154 pathway-sparing regimens can promote xenoislet survival. Further optimization of these strategies is warranted to aid the clinical translation of islet xenotransplantation. Immunosuppressive therapies that block the CD40/CD154 costimulatory pathway have proven to be uniquely effective in preclinical xenotransplant models. Given the challenges facing clinical translation of CD40/CD154 pathway blockade, we examined the efficacy and tolerability of CD40/CD154 pathway-sparing immunomodulatory strategies in a pig-to-nonhuman primate islet xenotransplant model. Rhesus macaques were rendered diabetic with streptozocin and given an intraportal infusion of ∼50 000 islet equivalents/kg wild-type neonatal porcine islets. Base immunosuppression for all recipients included maintenance therapy with belatacept and mycophenolate mofetil plus induction with basiliximab and LFA-1 blockade. Cohort 1 recipients (n = 3) were treated with the base regimen alone; cohort 2 recipients (n = 5) were additionally treated with tacrolimus induction and cohort 3 recipients (n = 5) were treated with alefacept in place of basiliximab, and more intense LFA-1 blockade. Three of five recipients in both cohorts 2 and 3 achieved sustained insulin-independent normoglycemia (median rejection-free survivals 60 and 111 days, respectively), compared to zero of three recipients in cohort 1. These data show that CD40/CD154 pathway-sparing regimens can promote xenoislet survival. Further optimization of these strategies is warranted to aid the clinical translation of islet xenotransplantation.

Xenotransplantation

Basiliximab

Belatacept

Immunosuppression

Abatacept

Tolerability

10.1111/j.1600-6143.2012.04031.x

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Citations (78)

311.4: Every 2-Month Belatacept Maintenance Therapy in Kidney Transplant Recipients: 3-Year Follow-up of a Randomized, Non-inferiority Trial

Transplantation (2022)

Aileen C. Johnson Geeta Karadkhele Neeta Shenvi Kirk A. Easley Christian P. Larsen

Introduction: Maintenance immunosuppression with belatacept following kidney transplantation results in improved long-term graft function as compared to calcineurin inhibitors. However, broad application of belatacept has been limited, in part related to logistical barriers surrounding a monthly (q1m) IV infusion requirement. Our center conducted a randomized, non-inferiority trial comparing every 2-month (q2m) dosing to standard q1m maintenance. At twelve month follow up, q2m dosing was noninferior to standard q1m dosing as determined by renal function (eGFR). Two-month dosing was safe and well tolerated without a significant incidence of immunologic events in subjects adherent to the study protocol, but longer term follow-up is of interest to better elucidate patient and graft outcomes. Here, we present the 3-year outcomes from this study. Methods: Low immunologic risk, stable renal transplant recipients a minimum of 1 year post-transplant were randomized to q1m or q2m belatacept maintenance therapy. 36-month follow-up was conducted as intention-to-treat on the population that initiated the study protocol. An autoregressive model using baseline-adjusted means with a random effect for subject was used to compare renal function between groups. Kaplan Meier survival analysis was performed for analysis of adverse and immunologic events. Results: 163 patients initiated the study protocol and received treatment in the q1m control group (n=82) or q2m study group (n=81). Renal allograft function as measured by baseline adjusted eGFR was not significantly different between groups at 36 months (mean [95% CI], q1m: 73.43[70.37, 76.49] vs. q2m: 72.46[69.08, 75.84].There were no statistically significant differences in time to death or graft loss (cumulative survival at 36 months, q1m: 92.6%, q2m: 95.0%, p=0.49; freedom from rejection (q1m: 98.7%, q2m: 92.4%, p=0.06), or freedom from DSA (q1m: 98.7%, q2m: 92.4%, p=0.06). During the extended 12-36 month follow-up period, 3 deaths, 1 graft loss occurred in the q1m group, compared to 2 deaths, 2 graft losses in the q2m group. In the q1m group, one patient developed DSA and acute rejection. In the q2m group, 3 patients developed DSA, 2 associated with acute rejection. All acute rejections in both groups were associated with documented medication nonadherence.Conclusions: Based on similar renal function and adverse event rates at 36 months compared to q1m, q2m belatacept is a viable and safe maintenance immunosuppressive strategy in low immunologic risk kidney transplant recipients with potential to facilitate increased clinical utilization of costimulation blockade-based immunosuppression. (ClinicalTrials.gov NCT02560558) James O. Robbins Foundation. James M. Cox Foundation. Carlos and Marguerite Mason Trust.

Belatacept

Immunosuppression

Post-hoc analysis

Cumulative incidence

Maintenance therapy

10.1097/01.tp.0000886380.49829.f4

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Citations (0)

A Novel Monoclonal Antibody to CD40 Prolongs Islet Allograft Survival

American Journal of Transplantation (2012)

Michael Lowe I. Raul Badell P. W. Thompson Benjamin Martin F. Leopardi

Basiliximab

CD154

Keyhole limpet hemocyanin

Immunosuppression

10.1111/j.1600-6143.2012.04054.x

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Citations (79)

CTLA4Ig Prevents Alloantibody Formation Following Nonhuman Primate Islet Transplantation Using the CD40-Specific Antibody 3A8

American Journal of Transplantation (2012)

I. Raul Badell Maria C. Russell Kenneth Cardona Virginia Shaffer A.P. Turner

Islet transplantation to treat type 1 diabetes has been limited in part by toxicities of current immunosuppression and recipient humoral sensitization. Blockade of the CD28/CD80/86 and CD40/CD154 pathways has shown promise to remedy both these limitations, but translation has been hampered by difficulties in translating CD154-directed therapies. Prior CD40-directed regimens have led to prolonged islet survival, but fail to prevent humoral allosensitization. We therefore evaluated the addition of CTLA4Ig to a CD40 blockade-based regimen in nonhuman primate (NHP) alloislet transplantation. Diabetic rhesus macaques were transplanted allogeneic islets using the CD40-specific antibody 3A8, basiliximab induction, and sirolimus with or without CTLA4Ig maintenance therapy. Allograft survival was determined by fasting blood glucose levels and flow cytometric techniques were used to test for donor-specific antibody (DSA) formation. CTLA4Ig plus 3A8, basiliximab and sirolimus was well tolerated and induced long-term islet allograft survival. The addition of CTLA4Ig prevented DSA formation, but did not facilitate withdrawal of the 3A8-based regimen. Thus, CTLA4Ig combines with a CD40-specific regimen to prevent DSA formation in NHPs, and offers a potentially translatable calcineurin inhibitor-free protocol inclusive of a single investigational agent for use in clinical islet transplantation without relying upon CD154 blockade.

Basiliximab

Immunosuppression

CD154

Regimen

Sirolimus

10.1111/j.1600-6143.2012.04029.x

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Citations (46)

False-positive leishmania serology in castleman's disease

Clinical Microbiology Newsletter (1994)

N. Cardeñosa Carmen Muñoz Guillem Prats I. Raul Badell Jaime Rotés Querol

10.1016/0196-4399(94)90061-2

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Citations (0)

Selective CD28 blockade attenuates CTLA-4–dependent CD8+ memory T cell effector function and prolongs graft survival

JCI Insight (2018)

Danya Liu I. Raul Badell Mandy L. Ford

Memory T cells pose a significant problem to successful therapeutic control of unwanted immune responses during autoimmunity and transplantation, as they are differentially controlled by cosignaling receptors such as CD28 and CTLA-4. Treatment with abatacept and belatacept impede CD28 signaling by binding to CD80 and CD86, but they also have the unintended consequence of blocking the ligands for CTLA-4, a process that may inadvertently boost effector responses. Here, we show that a potentially novel anti-CD28 domain antibody (dAb) that selectively blocks CD28 but preserves CTLA-4 coinhibition confers improved allograft survival in sensitized recipients as compared with CTLA-4 Ig. However, both CTLA-4 Ig and anti-CD28 dAb similarly and significantly reduced the accumulation of donor-reactive CD8+ memory T cells, demonstrating that regulation of the expansion of CD8+ memory T cell populations is controlled in part by CD28 signals and is not significantly impacted by CTLA-4. In contrast, selective CD28 blockade was superior to CTLA-4 Ig in inhibiting IFN-γ, TNF, and IL-2 production by CD8+ memory T cells, which in turn resulted in reduced recruitment of innate CD11b+ monocytes into allografts. Importantly, this superiority was CTLA-4 dependent, demonstrating that effector function of CD8+ memory T cells is regulated by the balance of CD28 and CTLA-4 signaling.

CD80

CTLA-4

CD86

Abatacept

Belatacept

Co-stimulation

Memory T cell

10.1172/jci.insight.96378

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Citations (23)

Transplant

Springer eBooks (2023)

Abraham J. Matar Brendan P. Lovasik William H. Kitchens I. Raul Badell

Embryology

10.1007/978-3-031-25596-0_32

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Citations (0)

[Mixed acute leukemia: T lymphoblastic and monoblastic].

PubMed (1987)

C. Guañabens Silvestre Oltra E Rubiol Assumpció Bosch I. Raul Badell

Source

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CMV high-risk status and posttransplant outcomes in kidney transplant recipients treated with belatacept

American Journal of Transplantation (2020)

Geeta Karadkhele Julien Hogan Wairimu Magua Weiwen Zhang I. Raul Badell

Cytomegalovirus (CMV) remains associated with poor outcomes after kidney transplantation (kTx). The impact of belatacept on CMV infection remains understudied. In this study, we assessed the impact of belatacept on patient and graft survivals.CMV seronegative kTx recipients were included. Patient and graft survival were studied using Kaplan-Meier method, log-rank test. Cox models were used to compare outcomes by CMV risk and immunosuppressive regimen. Incidence and persistence of CMV viremia under belatacept vs tacrolimus were compared.Among 308 CMV seronegative recipients, 168 CMV high-risk and 203 belatacept-treated patients were included. High-risk CMV status was associated with lower patient survival and graft survival. Among the CMV high-risk group, patients treated with belatacept presented a higher incidence of CMV viremia, a higher rate of first-line treatment failure and a longer time to virus clearance. They had a nonsignificant trend toward a lower graft survival.Belatacept-based maintenance immunosuppression is associated with an increased risk of CMV primary-infection and a prolonged course of viral replication in CMV high-risk patients. Further studies are needed to confirm the nonsignificant trend towards a lower graft survival in CMV high-risk patients treated with belatacept and whether it is explained by the higher risk of CMV reactivation and infection.

Belatacept

Immunosuppression

Viremia

Regimen

10.1111/ajt.16132

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Citations (59)