Targeting of B and T lymphocyte associated (BTLA) prevents graft-versus-host disease without global immunosuppression

Albring, Jörn; Sandau, Michelle M.; Rapaport, Aaron S.; Edelson, Brian T.; Satpathy, Ansuman T.; Mashayekhi, Mona; Lathrop, Stephanie K.; Hsieh, Chyi-Song; Stelljes, Matthias; Colonna, Marco; Murphy, Theresa L.

doi:10.1084/jem.20102017

Cited by 59 publications

(62 citation statements)

References 37 publications

(72 reference statements)

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“…Especially, in the allo-SCT setting, interference with coinhibitory molecules could deteriorate GVHD. In mouse models, however, BTLA has been reported to have a differential role in GVT responses, and not in GVHD (40,41). Although we found high expression of both BTLA and PD-1 on MiHA-specific CD8 + T cells, we could not correlate their expression levels to the effect on T cell proliferation upon blocking of either of these pathways (data not shown).…”

Section: Discussionmentioning

confidence: 59%

“…Importantly, blocking of BTLA results in enhanced outgrowth of MiHA-specific cells upon DC stimulation. Moreover, others reported a differential role of BTLA in the induction of GVHD and GVT responses (40,41), making it an interesting target to prevent adverse alloreactive effects. This prompts BTLA as a novel target in combination with DC vaccination.…”

Section: Discussionmentioning

confidence: 99%

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B and T Lymphocyte Attenuator Mediates Inhibition of Tumor-Reactive CD8+ T Cells in Patients After Allogeneic Stem Cell Transplantation

Hobo

Norde

Schaap

et al. 2012

The Journal of Immunology

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Allogeneic stem cell transplantation (allo-SCT) can cure hematological malignancies by inducing alloreactive T cell responses targeting minor histocompatibility antigens (MiHA) expressed on malignant cells. Despite induction of robust MiHA-specific T cell responses and long-term persistence of alloreactive memory T cells specific for the tumor, often these T cells fail to respond efficiently to tumor relapse. Previously, we demonstrated the involvement of the coinhibitory receptor programmed death-1 (PD-1) in suppressing MiHA-specific CD8+ T cell immunity. In this study, we investigated whether B and T lymphocyte attenuator (BTLA) plays a similar role in functional impairment of MiHA-specific T cells after allo-SCT. In addition to PD-1, we observed higher BTLA expression on MiHA-specific CD8+ T cells compared with that of the total population of CD8+ effector-memory T cells. In addition, BTLA’s ligand, herpes virus entry mediator (HVEM), was found constitutively expressed by myeloid leukemia, B cell lymphoma, and multiple myeloma cells. Interference with the BTLA–HVEM pathway, using a BTLA blocking Ab, augmented proliferation of BTLA+PD-1+ MiHA-specific CD8+ T cells by HVEM-expressing dendritic cells. Notably, we demonstrated that blocking of BTLA or PD-1 enhanced ex vivo proliferation of MiHA-specific CD8+ T cells in respectively 7 and 9 of 11 allo-SCT patients. Notably, in 3 of 11 patients, the effect of BTLA blockade was more prominent than that of PD-1 blockade. Furthermore, these expanded MiHA-specific CD8+ T cells competently produced effector cytokines and degranulated upon Ag reencounter. Together, these results demonstrate that BTLA–HVEM interactions impair MiHA-specific T cell functionality, providing a rationale for interfering with BTLA signaling in post-stem cell transplantation therapies.

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Section: Discussionmentioning

confidence: 59%

Section: Discussionmentioning

confidence: 99%

B and T Lymphocyte Attenuator Mediates Inhibition of Tumor-Reactive CD8+ T Cells in Patients After Allogeneic Stem Cell Transplantation

Hobo

Norde

Schaap

et al. 2012

The Journal of Immunology

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“…6 Importantly, BTLA is expressed by naive CD4 1 and CD8 1 T cells, the T-cell compartments known to be enriched for alloreactive specificity, and agonistic antibodymediated BTLA stimulation reduces donor T-cell-mediated acute GVHD in murine transplant models, consistent with a functional role for BTLA in controlling donor T-cell alloresponses in this setting. [8][9][10] Activated FL B cells can act as potent alloantigen-presenting cells in vitro 11 and patients with FL often undergo AHSCT with significant residual lymphoma. We hypothesized that TNFRSF14 aberrations would reduce expression of HVEM and increase the ability of FL B cells to stimulate allogeneic T-cell responses.…”

Section: Introductionmentioning

confidence: 99%

TNFRSF14 aberrations in follicular lymphoma increase clinically significant allogeneic T-cell responses

Kotsiou

Okosun

Besley

et al. 2016

Blood

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Key Points• TNFRSF14 gene aberrations, common in FL, increase the ability of lymphoma cells to stimulate allogeneic T-cell responses.• TNFRSF14 lesions were associated with increased acute GVHD supporting stratified transplantation approaches in the allogeneic setting.Donor T-cell immune responses can eradicate lymphomas after allogeneic hematopoietic stem cell transplantation (AHSCT), but can also damage healthy tissues resulting in harmful graftversus-host disease (GVHD). Next-generation sequencing has recently identified many new genetic lesions in follicular lymphoma (FL). One such gene, tumor necrosis factor receptor superfamily 14 (TNFRSF14), abnormal in 40% of FL patients, encodes the herpes virus entry mediator (HVEM) which limits T-cell activation via ligation of the B-and T-lymphocyte attenuator.As lymphoma B cells can act as antigen-presenting cells, we hypothesized that TNFRSF14 aberrations that reduce HVEM expression could alter the capacity of FL B cells to stimulate allogeneic T-cell responses and impact the outcome of AHSCT. In an in vitro model of alloreactivity, human lymphoma B cells with TNFRSF14 aberrations had reduced HVEM expression and greater alloantigen-presenting capacity than wild-type lymphoma B cells. The increased immune-stimulatory capacity of lymphoma B cells with TNFRSF14 aberrations had clinical relevance, associating with higher incidence of acute GVHD in patients undergoing AHSCT. FL patients with TNFRSF14 aberrations may benefit from more aggressive immunosuppression to reduce harmful GVHD after transplantation. Importantly, this study is the first to demonstrate the impact of an acquired genetic lesion on the capacity of tumor cells to stimulate allogeneic T-cell immune responses which may have wider consequences for adoptive immunotherapy strategies. (Blood. 2016;128(1):72-81)

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“…In agreement with the concept that BTLA functions as a prosurvival molecule for T cells is the fact that the engagement of BTLA on donor alloreactive T cells is required for their survival in a graft versus host disease murine model. 46,51 Thus, a single injection of an agonistic anti-BTLA antibody (clone 6A6) at the time of allogeneic bone marrow transplantation was sufficient to prevent GvHD through a mechanism that was mediated by donor Tregs. 51,52 The agonistic effect of the anti-BTLA antibody treatment and not the blockade of the interaction of HVEM/ BTLA on donor CD4 effector cells promoted a rapid contraction of the CD4 T-cell-mediated allogeneic immune response due to impaired survival of donor T cells expanding in response to lymphopenia in conditioned hosts and to an advantageous and competitive homeostatic expansion of Tregs that were responsible for prevention of the disease.…”

Section: Discussionmentioning

confidence: 99%

“…46,51 Thus, a single injection of an agonistic anti-BTLA antibody (clone 6A6) at the time of allogeneic bone marrow transplantation was sufficient to prevent GvHD through a mechanism that was mediated by donor Tregs. 51,52 The agonistic effect of the anti-BTLA antibody treatment and not the blockade of the interaction of HVEM/ BTLA on donor CD4 effector cells promoted a rapid contraction of the CD4 T-cell-mediated allogeneic immune response due to impaired survival of donor T cells expanding in response to lymphopenia in conditioned hosts and to an advantageous and competitive homeostatic expansion of Tregs that were responsible for prevention of the disease. 51 Tregs have also been implicated in the regulation of the allogeneic response in CBA mice receiving a heart allograft from B6 donors treated with an agonistic anti-BTLA antibody.…”

Section: Discussionmentioning

confidence: 99%

T follicular helper expansion and humoral-mediated rejection are independent of the HVEM/BTLA pathway

et al. 2016

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Targeting of B and T lymphocyte associated (BTLA) prevents graft-versus-host disease without global immunosuppression

Abstract: One-time treatment with an antibody against BTLA provides long-term protection against graft-versus-host disease without affecting effector T cell responses to tumors or pathogens.

Cited by 59 publications

References 37 publications

B and T Lymphocyte Attenuator Mediates Inhibition of Tumor-Reactive CD8+ T Cells in Patients After Allogeneic Stem Cell Transplantation

B and T Lymphocyte Attenuator Mediates Inhibition of Tumor-Reactive CD8+ T Cells in Patients After Allogeneic Stem Cell Transplantation

TNFRSF14 aberrations in follicular lymphoma increase clinically significant allogeneic T-cell responses

T follicular helper expansion and humoral-mediated rejection are independent of the HVEM/BTLA pathway

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