An Acute Cellular Rejection With Detrimental Outcome Occurring Under Belatacept-Based Immunosuppressive Therapy

Graav, Gretchen N. de; Hesselink, Dennis A.; Dieterich, M.; Kraaijeveld, Rens; Douben, Hannie; Klein, Annelies de; Roelen, Dave L.; Weimar, Willem; Roodnat, Joke I.; Groningen, Marian C. Clahsen-van; Baan, Carla C.

doi:10.1097/tp.0000000000001004

Cited by 25 publications

(28 citation statements)

References 25 publications

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“…Becausce CD4 + CD28 null T cells need additional cytokines next to allogeneic stimulation, inhibition of immune cells that can provide these cytokines will lead to a low alloresponsive state. In costimulatory blockade–resistant rejections, however, rejections are more serious compared with rejections under cyclosporine . A study by de Graav et al.…”

Section: Discussionmentioning

confidence: 99%

CD4+CD28null T cells are not alloreactive unless stimulated by interleukin-15

Dedeoğlu

Litjens

Klepper

et al. 2018

American Journal of Transplantation

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Proinflammatory, cytotoxic CD4 CD28 T cells can be substantially expanded in patients with end-stage renal disease. These cells have been associated with the risk for rejection, but their alloreactive potential is unknown. CD4 CD28 T cells were stimulated with HLA-mismatched antigen presenting cells in the absence/presence of exogenous cytokines. Alloreactive potential was evaluated based on proliferation, degranulation, cytotoxicity, and cytokine production. Further, their suppressive capacity was assessed by measuring inhibition of proliferating alloreactive CD28 T cells. CD4 CD28 T cells contained alloreactive (CD137 ) T cells but did not proliferate in response to allogeneic stimulation, unless interleukin (IL)-15 was added. However, they could proliferate on stimulation with cytomegalovirus antigen without exogenous cytokines. IL-15 increased the frequency of proliferating alloreactive CD4 CD28 T cells to 30.5% without inducing CD28 expression (P < .05). After allogeneic stimulation together with IL-15 and IL-21, frequency of degranulating CD107a CD4 CD28 T cells increased significantly from 0.6% to 5.8% (P < .001). Granzyme B and perforin positivity remained similar, but production of interferon-γ and tumor necrosis factor-α increased by the combination of IL-15 and IL-21 (P < .001 and P < .05, respectively). Finally, CD4 CD28 T cells did not show significant suppression. Thus, CD4 CD28 T cells represent a population with absent alloreactivity unless IL-15 is present.

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Section: Discussionmentioning

confidence: 99%

CD4+CD28null T cells are not alloreactive unless stimulated by interleukin-15

Dedeoğlu

Litjens

Klepper

et al. 2018

American Journal of Transplantation

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“…However, these findings were not confirmed in recent randomized controlled clinical trials in which belataceptbased immunosuppressive therapy was compared with tacrolimus-based immunosuppressive therapy [21][22][23]. In the study by de Graav et al, 11 of the 20 (55%) belatacepttreated patients experienced biopsy-proven acute rejection (BPAR) compared with two of 20 in the control arm [12,23], while in another study patient enrolment was even halted because of a high rate of acute cellular rejection [21]. In the study by de Graav et al [23], no association between rejection and higher frequencies of CD4 1 CD57 1 PD-1was found.…”

Section: Introductionmentioning

confidence: 96%

“…Immune activation of CD28 1 T cells via T cell receptors without a co-stimulatory signal during belatacept treatment results in anergy [6,7]. It has been hypothesized that these CD28memory T cells are responsible for the increased rejection risk of patients treated with belatacept [11,12]. It has been hypothesized that these CD28memory T cells are responsible for the increased rejection risk of patients treated with belatacept [11,12].…”

Section: Introductionmentioning

confidence: 99%

“…CD4 1 CD57 1 T cells were also found to infiltrate the kidney allograft during rejection, and genes involved in allograft rejection were up-regulated in this T cell subset [20]. In the study by de Graav et al, 11 of the 20 (55%) belatacepttreated patients experienced biopsy-proven acute rejection (BPAR) compared with two of 20 in the control arm [12,23], while in another study patient enrolment was even halted because of a high rate of acute cellular rejection [21]. In the study by de Graav et al, 11 of the 20 (55%) belatacepttreated patients experienced biopsy-proven acute rejection (BPAR) compared with two of 20 in the control arm [12,23], while in another study patient enrolment was even halted because of a high rate of acute cellular rejection [21].…”

Section: Introductionmentioning

confidence: 99%

“…However, antigen-experienced T cells down-regulate CD28 [8] and are therefore able to escape co-stimulatory blockade by belatacept [9,10]. It has been hypothesized that these CD28memory T cells are responsible for the increased rejection risk of patients treated with belatacept [11,12]. The vast majority of these CD28cells express CD57, a marker expressed by natural killer (NK) cells and T cells [13] which is used to identify terminally differentiated senescent cells with reduced proliferative capacity [14].…”

Section: Introductionmentioning

confidence: 99%

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Co-inhibitory profile and cytotoxicity of CD57+PD-1− T cells in end-stage renal disease patients

Kraaijeveld

Graav

Dieterich

et al. 2017

Clinical and Experimental Immunology

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Blockade of the CD80/86-CD28 pathway by belatacept after kidney transplantation is associated with an increased risk of rejection compared with standard, calcineurin inhibitor (CNI)-based therapy. CD28 T cells, which express CD57, are not susceptible to belatacept treatment. High numbers of CD4 CD57 programmed death 1 (PD-1) T cells pretransplantation have been associated with a higher chance of rejection, although conflicting data have been reported. To investigate the working mechanism behind this possible higher chance of rejection, we studied the expression of co-inhibitory molecules (CD223, CD244 and PD-1), proliferative capacity and cytotoxic potential of fluorescence activated cell sorted (FACS) CD4 CD57 PD-1 and CD8 CD57 PD-1 T cells, and their CD57 control populations, after alloantigen stimulation. The effect of belatacept on the cytotoxic capacity of pretransplantation peripheral blood mononuclear cells from 20 patients who received belatacept post-transplantation was also tested. Expression of co-inhibitory molecule CD223 increased by approximately 10-fold after allogeneic stimulation in all four T cell subsets. Proliferation and up-regulation of CD244 and PD-1 was observed for CD4 CD57 PD-1 T cells after allogeneic stimulation, but no up-regulation of these markers occurred on CD8 T cells or CD4 CD57 PD-1 T cells. However, CD4 CD57 PD-1 T cells and, to a lesser extent, CD8 CD57 PD-1 T cells displayed higher cytotoxicity as indicated by granzyme B expression. Belatacept inhibited the cytotoxic potential of CD4 CD57 PD-1 T cells (median of inhibition 31%, P < 0·01) and CD8 CD57 PD-1 T cells (median of inhibition 10%, P < 0·05). In conclusion, alloantigen-activated CD4 CD57 PD-1 T cells exhibited a less proliferative but more cytotoxic profile than their CD57 counterparts. Their cytotoxic capacity can be inhibited partly by belatacept and was not associated with development of rejection after kidney transplantation.

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Co-stimulation Blockade Plus T-Cell Depletion in Transplant Patients: Towards a Steroid- and Calcineurin Inhibitor-Free Future?

Herr

Brunel

Roders

et al. 2016

Drugs

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Long-term survival of solid allografts depends on both immunosuppressive efficacy and reducing the side effects associated with these therapies. Immunotherapies developed over the past 15 years to prevent organ rejection have greatly improved cardiovascular and renal function compared with classical therapies, such as calcineurin inhibitors and corticosteroids. Immunotherapies that target T cells through the co-stimulation blockade (CTLA-4-Ig) improve renal function and the survival of grafts and patients, but are associated with higher rates of T-cell-mediated acute rejection. Improvements to safe and efficacious therapeutic options could combine a co-stimulation blockade with a depleting immunotherapy. Herein, we describe the clinical outcomes and the likely causes of defects in the co-stimulation blockade, and comment on new therapeutic strategies to overcome these. Great progress has been made to optimize immunotherapy using the co-stimulation blockade, but the therapeutic combinations should be assessed further.

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An Acute Cellular Rejection With Detrimental Outcome Occurring Under Belatacept-Based Immunosuppressive Therapy

Abstract: We postulate that this glucocorticoid-resistant cellular rejection occurring under belatacept was predominantly mediated by cytotoxic memory T cells, which are less susceptible to costimulatory blockade by belatacept, or resulted from incomplete CD80/86 blockade at the tissue level.

Cited by 25 publications

References 25 publications

CD4+CD28null T cells are not alloreactive unless stimulated by interleukin-15

CD4+CD28null T cells are not alloreactive unless stimulated by interleukin-15

Co-inhibitory profile and cytotoxicity of CD57+PD-1− T cells in end-stage renal disease patients

Co-stimulation Blockade Plus T-Cell Depletion in Transplant Patients: Towards a Steroid- and Calcineurin Inhibitor-Free Future?

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