T cells expressing chimeric antigen receptor promote immune tolerance
Antonio Pierini, Bettina P. Iliopoulou, Heshan Peiris, Magdiel Pérez-Cruz, Jeanette Baker, Katie Hsu, Xueying Gu, Ping-Ping Zheng, Tom Erkers, Sai-Wen Tang, William Strober, Maite Alvarez, Aaron Ring, Andrea Velardi, Robert S. Negrin, Seung K. Kim, Everett H. Meyer
Antonio Pierini, Bettina P. Iliopoulou, Heshan Peiris, Magdiel Pérez-Cruz, Jeanette Baker, Katie Hsu, Xueying Gu, Ping-Ping Zheng, Tom Erkers, Sai-Wen Tang, William Strober, Maite Alvarez, Aaron Ring, Andrea Velardi, Robert S. Negrin, Seung K. Kim, Everett H. Meyer
View: Text | PDF
Research Article Immunology Transplantation

T cells expressing chimeric antigen receptor promote immune tolerance

Abstract

Cellular therapies based on permanent genetic modification of conventional T cells have emerged as a promising strategy for cancer. However, it remains unknown if modification of T cell subsets, such as Tregs, could be useful in other settings, such as allograft transplantation. Here, we use a modular system based on a chimeric antigen receptor (CAR) that binds covalently modified mAbs to control Treg activation in vivo. Transient expression of this mAb-directed CAR (mAbCAR) in Tregs permitted Treg targeting to specific tissue sites and mitigated allograft responses, such as graft-versus-host disease. mAbCAR Tregs targeted to MHC class I proteins on allografts prolonged islet allograft survival and also prolonged the survival of secondary skin grafts specifically matched to the original islet allograft. Thus, transient genetic modification to produce mAbCAR T cells led to durable immune modulation, suggesting therapeutic targeting strategies for controlling alloreactivity in settings such as organ or tissue transplantation.

Authors

Antonio Pierini, Bettina P. Iliopoulou, Heshan Peiris, Magdiel Pérez-Cruz, Jeanette Baker, Katie Hsu, Xueying Gu, Ping-Ping Zheng, Tom Erkers, Sai-Wen Tang, William Strober, Maite Alvarez, Aaron Ring, Andrea Velardi, Robert S. Negrin, Seung K. Kim, Everett H. Meyer

×

Figure 7

FITC-H-2Dd-mAbCAR Tregs acquire antigen specificity after in vivo transfer.

Options: View larger image (or click on image) Download as PowerPoint
FITC-H-2Dd-mAbCAR Tregs acquire antigen specificity after in vivo transf...
(A) Experimental scheme. Mice that were previously transplanted with allogeneic pancreatic islet graft in the left kidney capsule received a secondary double skin graft MHC matched with the previously transplanted pancreatic graft (upper grafts) or “third party” (lower grafts). Data are representative of 2 consecutive experiments; at least 4 mice/group were used. Skins have been also transplanted in inverted position (“third-party” skins as upper grafts and MHC-matched skins as lower graft) in order to avoid technical bias. (B) Mice treated with FITC-H-2Dd-mAbCAR Tregs show alloantigen-specific protection of matched skin grafts. Survival of the skin graft that was MHC matched with the previously transplanted allogeneic islet graft in mice that received no Treg treatment (black squares), or FITC-isotype-mAbCAR Tregs (blue squares), or FITC-H-2Dd-mAbCAR Tregs (red squares). Log-rank survival test; *P < 0.05 is reported for differences between the group that received FITC-H-2Dd-mAbCAR Tregs versus the group that received no Treg treatment or FITC-isotype-mAbCAR Tregs. (C) FITC-H-2Dd-mAbCAR Tregs do not protect “third-party” skin grafts. Survival of the skin graft that was “third-party” with the previously transplanted allogeneic islet graft and the infused Tregs in mice that received no Treg treatment (black squares), or FITC-isotype-mAbCAR Tregs (blue squares), or FITC-H-2Dd-mAbCAR Tregs (red squares). Log-rank survival test; no statistical significance was detected between the three groups.