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CD28 blockade controls T cell activation to prevent graft-versus-host disease in primates
Benjamin K. Watkins, … , Bernard Vanhove, Leslie S. Kean
Benjamin K. Watkins, … , Bernard Vanhove, Leslie S. Kean
Published August 13, 2018
Citation Information: J Clin Invest. 2018;128(9):3991-4007. https://doi.org/10.1172/JCI98793.
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Research Article Immunology Transplantation

CD28 blockade controls T cell activation to prevent graft-versus-host disease in primates

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Abstract

Controlling graft-versus-host disease (GVHD) remains a major unmet need in stem cell transplantation, and new, targeted therapies are being actively developed. CD28-CD80/86 costimulation blockade represents a promising strategy, but targeting CD80/CD86 with CTLA4-Ig may be associated with undesired blockade of coinhibitory pathways. In contrast, targeted blockade of CD28 exclusively inhibits T cell costimulation and may more potently prevent GVHD. Here, we investigated FR104, an antagonistic CD28-specific pegylated-Fab′, in the nonhuman primate (NHP) GVHD model and completed a multiparameter interrogation comparing it with CTLA4-Ig, with and without sirolimus, including clinical, histopathologic, flow cytometric, and transcriptomic analyses. We document that FR104 monoprophylaxis and combined prophylaxis with FR104/sirolimus led to enhanced control of effector T cell proliferation and activation compared with the use of CTLA4-Ig or CTLA4-Ig/sirolimus. Importantly, FR104/sirolimus did not lead to a beneficial impact on Treg reconstitution or homeostasis, consistent with control of conventional T cell activation and IL-2 production needed to support Tregs. While FR104/sirolimus had a salutary effect on GVHD-free survival, overall survival was not improved, due to death in the absence of GVHD in several FR104/sirolimus recipients in the setting of sepsis and a paralyzed INF-γ response. These results therefore suggest that effectively deploying CD28 in the clinic will require close scrutiny of both the benefits and risks of extensively abrogating conventional T cell activation after transplant.

Authors

Benjamin K. Watkins, Victor Tkachev, Scott N. Furlan, Daniel J. Hunt, Kayla Betz, Alison Yu, Melanie Brown, Nicolas Poirier, Hengqi Betty Zheng, Agne Taraseviciute, Lucrezia Colonna, Caroline Mary, Gilles Blancho, Jean-Paul Soulillou, Angela Panoskaltsis-Mortari, Prachi Sharma, Anapatricia Garcia, Elizabeth Strobert, Kelly Hamby, Aneesah Garrett, Taylor Deane, Bruce R. Blazar, Bernard Vanhove, Leslie S. Kean

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Figure 9

The impact of FR104/sirolimus on Treg homeostasis after transplant.

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The impact of FR104/sirolimus on Treg homeostasis after transplant.
(A) ...
(A) The relative number (percentage of total CD4 T cells; top panel), the absolute number (middle panel), and the Treg/100 Tconv ratio, normalized to the corresponding pretransplant values (bottom panel) were tracked longitudinally by flow cytometry in the No Rx (n = 7), sirolimus (n = 6), FR104 (n = 3), FR104/sirolimus (n = 9), and CTLA4-Ig/sirolimus (n = 7) cohorts. Tregs were defined as CD3+CD4+CD25+CD127loFoxP3+; Tconv cells were defined as CD3+CD8+ and CD3+CD4+CD25–CD127hi by flow cytometric analysis. Data are shown as mean ± SEM. The solid red threshold line represents the Treg/100 Tconv ratio in the No Rx cohort at terminal analysis (62), with dotted lines above and below the threshold line representing the SEM interval. (B) The relative number (percentage of total CD4+ T cells) of Tregs in the peripheral (axillary and inguinal) LNs and spleen in HC animals and recipients from KY1005/sirolimus undergoing terminal analysis before or after day 66. (C) The normalized Treg/100 Tconv ratio (left panel) and the percentage of CD28+CD4+ T cells (right panel) before (white circles) and after (black circles) discontinuation of FR104 in FR104/sirolimus cohort recipients who survived more than 66 days after transplant (R.249, R.250, and R.251). Each line represents a single experiment.
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