Outcomes in transplantation have been limited by suboptimal long-term graft survival and toxicities associated with current immunosuppressive approaches. T cell costimulation blockade has shown promise as an alternative strategy to avoid the side effects of conventional immunosuppressive therapies, but targeting CD28-mediated costimulation alone has proven insufficient to prevent graft rejection in primates. Donor-specific memory T (TM) cells have been implicated in costimulation blockade-resistant transplant rejection, due to their enhanced effector function and decreased reliance on costimulatory signaling. Thus, we have tested a potential strategy to overcome TM cell-driven rejection by targeting molecules preferentially expressed on these cells, such as the adhesion molecule lymphocyte function-associated antigen 1 (LFA-1). Here, we show that short-term treatment (i.e., induction therapy) with the LFA-1-specific antibody TS-1/22 in combination with either basiliximab (an IL-2Rα-specific mAb) and sirolimus (a mammalian target of rapamycin inhibitor) or belatacept (a high-affinity variant of the CD28 costimulation-blocker CTLA4Ig) prolonged islet allograft survival in nonhuman primates relative to control treatments. Moreover, TS-1/22 masked LFA-1 on TM cells in vivo and inhibited the generation of alloproliferative and cytokine-producing effector T cells that expressed high levels of LFA-1 in vitro. These results support the use of LFA-1-specific induction therapy to neutralize costimulation blockade-resistant populations of T cells and further evaluation of LFA-1-specific therapeutics for use in transplantation.

Belatacept

Basiliximab

Abatacept

10.1172/jci43895

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Citations (108)

Impact of belatacept and tacrolimus on cytomegalovirus viral load control and relapse in moderate and high‐risk cytomegalovirus serostatus kidney transplant recipients

Transplant Infectious Disease (2022)

Wairimu Magua Aileen C. Johnson Geeta Karadkhele I. Raul Badell Payaswini Vasanth

Abstract Background Belatacept improves long‐term graft survival, but control of some primary viral infections may be impaired. We evaluated the impact of belatacept and tacrolimus on cytomegalovirus (CMV) viral control, remission and relapse in CMV high‐risk and moderate‐risk recipients. Methods Using a multistate Markov model, we evaluated viral load state transitions of 173 kidney transplant recipients with at least one episode of viremia within 1 year after transplant: state 1, undetectable/low viral load; state 2, moderate viremia; and state 3, severe viremia. Results Among high‐risk recipients, belatacept‐treated recipients exhibited a significantly higher probability of entering moderate viremia (.36; 95% CI = .31, .41) than tacrolimus‐treated recipients (.20; 95% CI = .13, .29). The expected number of days in viremic states differed. High‐risk belatacept‐treated recipients persisted in moderate viremia for significantly longer (128 days, 95% CI = 110, 146) than did tacrolimus‐treated recipients (70.0 days, 95% CI = 45.2, 100) and showed a trend of shorter duration in low/undetectable viral load state (172 days, 95% CI = 148, 195) than did tacrolimus‐treated recipients (239 days, 95% CI = 195, 277). Moderate‐risk recipients showed better viral load control and with no differences by immunosuppression. Conclusion High‐risk belatacept‐treated recipients showed defects in sustaining viral control relative to tacrolimus‐treated recipients. Avoidance of initial use belatacept in high‐risk recipients or development of modified management protocols should be considered. image

Belatacept

Viremia

Serostatus

Immunosuppression

Cytomegalovirus

10.1111/tid.13983

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Citations (6)

Temporal trends and current use of de novo belatacept in kidney transplant recipients in the United States

Clinical Transplantation (2021)

Geeta Karadkhele Charlotte Duneton Rouba Garro I. Raul Badell Thomas C. Pearson

The adoption of de novo belatacept in kidney transplant (kTx) recipients was hampered by an increased risk of acute cellular rejection (ACR) with variation in adopted belatacept based immunosuppressive therapies across centers. We used data from the Scientific Registry of Transplant Recipients (SRTR) to evaluate the temporal trends in belatacept use and describe the associated induction and maintenance regimens in US adult kTx recipients transplanted between June 2011 and December 2018. The number of patients receiving de novo-belatacept based immunosuppressive therapy increased from .74% in 2011 to 3.11% in 2016. In 2016, 66/207 centers used de novo belatacept-based regimen with 3.03% using it in over 50% of their patients. The use of T-cell depleting agents increased with time. Since 2012, the rate of calcineurin inhibitor (CNI) use in combination with belatacept remained stable around 50% and ∼30% remained under belatacept/CNI combination at 1-year post-transplantation. The adoption of belatacept as de novo immunosuppressive regimen has been slow and its use remains low in the United States. Various regimens have been used to modulate the risk of ACR. Further studies evaluating the long-term outcomes of these regimens and assessing their safety especially with regard to the risk of infection are needed.

Belatacept

Regimen

Abatacept

Immunosuppression

10.1111/ctr.14531

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Citations (11)

Costimulatory Blockade and Solid Organ Transplantation: The Past, Present, and Future

Kidney International Reports (2023)

William H. Kitchens Christian P. Larsen I. Raul Badell

Belatacept is the first costimulatory blockade agent clinically approved for transplant immunosuppression. Although more than 10 years of study have demonstrated that belatacept offers superior long-term renal allograft and patient survival compared to conventional calcineurin inhibitor (CNI)-based immunosuppression regimens, the clinical adoption of belatacept has continued to lag because of concerns of an early risk of acute cellular rejection (ACR) and various logistical barriers to its administration. In this review, the history of the clinical development of belatacept is examined, along with the findings of the seminal BENEFIT and BENEFIT-EXT trials culminating in the clinical approval of belatacept. Recent efforts to incorporate belatacept into novel CNI-free immunosuppression regimens are reviewed, as well as the experience of the Emory Transplant Center in using a tapered course of low-dose tacrolimus in belatacept-treated renal allograft patients to garner the long-term outcome benefits of belatacept without the short-term increased risks of ACR. Potential avenues to increase the clinical adoption of belatacept in the future are explored, including surmounting the logistical barriers of belatacept administration through subcutaneous administration or more infrequent belatacept dosing. In addition, belatacept conversion strategies and potential expanded clinical indications of belatacept are discussed for pediatric transplant recipients, extrarenal transplant recipients, treatment of antibody-mediated rejection (AMR), and in patients with failed renal allografts. Finally, we discuss the novel immunosuppressive drugs currently in the development pipeline that may aid in the expansion of costimulation blockade utilization.

Belatacept

Immunosuppression

Abatacept

10.1016/j.ekir.2023.08.037

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Citations (9)

[Congenital monoblastic leukemia and self-healing papulonodular cutaneous lesions].

PubMed (1990)

Ramón M. Pujol Diego Fabián Vique López I. Raul Badell M. Alejo Joaquim Soler

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Citations (2)

2B4 (CD244) Induced By Selective CD28 Blockade Functionally Regulates Allograft-Specific CD8+ T Cell Responses.

Transplantation (2014)

D. Liu Scott M. Krummey I. Raul Badell Maylene E. Wagener Lumelle A. Schneeweis

Mounting evidence in models of both autoimmunity and chronic viral infection suggests that the outcome of T cell activation is critically impacted by the constellation of costimulatory and coinhibitory receptors expressed on the cells' surface. Here, we identified a critical role for the coinhibitory SLAM family member 2B4 (CD244) in attenuating primary donor-reactive CD8+ T cell responses in the presence of immune modulation with selective CD28 blockade. Our results reveal a specific upregulation of 2B4 on donor-reactive CD8+ T cells in animals in which CD28 signaling was blocked. However, 2B4 upregulation was not observed in animals treated with CTLA-4 Ig (abatacept) or CD28 blockade in the presence of anti-CTLA-4 mAb, indicating that CTLA-4 coinhibitory signals are required for 2B4 upregulation. Skin graft experiments revealed a dramatic prolongation in survival in animals treated with CD28 dAbs, in which CTLA-4 coinhibitory signaling is maintained and 2B4 coinhibitory signaling is induced, as compared to CTLA-4 Ig in both major and minor histocompatibility models. Interestingly, the increased efficacy of CD28 dAbs in attenuating donor-reactive CD8+ T cell responses as compared to CTLA-4 Ig was not an effect of preserved PD-L1/CD80 coinhibitory signals, as blockade of PD-L1 did not abrogate the ability of CD28 dAb to inhibit donor-reactive CD8+ T cell responses or induce 2B4 upregulation. In order to directly assess the functional role of the 2B4 coinhibitory pathway in prolonging allograft survival, we assessed donor-reactive CD8+ T cell responses in 2B4-/- mice. 2B4 upregulation following CD28 blockade was functionally significant, as the inhibitory impact of CD28 blockade was diminished when donor-reactive CD8+ T cells were deficient in 2B4. In contrast, 2B4 deficiency had no effect on CD8+ T cell responses during unmodified rejection or in the presence of CTLA-4 Ig. We conclude that blockade of CD28 signals in the presence of preserved CTLA-4 signals results in the unique upregulation of 2B4 on primary CD8+ effectors, and that this 2B4 expression plays a critical functional role in controlling donor-reactive CD8+ T cell responses during transplantation. DISCLOSURES:Schneeweis, L.: Employee, Bristol Myers-Squibb. Stetsko, D.: Employee, Bristol Myers-Squibb. Suchard, S.: Employee, Bristol Myers-Squibb. Nadler, S.: Employee, Bristol Myers-Squibb.

CD80

CTLA-4

10.1097/00007890-201407151-01028

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Citations (1)

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

American Journal of Transplantation (2015)

I. Raul Badell William H. Kitchens Maylene E. Wagener Aron E. Lukacher Christian P. Larsen

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.

Memory T cell

Immunosuppression

10.1111/ajt.13399

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Citations (16)