Graft-infiltrating host dendritic cells play a key role in organ transplant rejection

Quan Zhuang; Quan Liu; Sherrie J. Divito; Qiang Zeng; Karim M. Yatim; Andrew D. Hughes; Darling M. Rojas-Canales; A. Nakao; William J. Shufesky; Amanda L. Williams; Rishab Humar; Rosemary A. Hoffman; Warren D. Shlomchik; Martin H. Oberbarnscheidt; Fadi G. Lakkis; Adrian E. Morelli

doi:10.1038/ncomms12623

Graft-infiltrating host dendritic cells play a key role in organ transplant rejection

Quan Zhuang, Quan Liu, Sherrie J. Divito, Qiang Zeng, Karim M. Yatim, Andrew D. Hughes, Darling M. Rojas-Canales, A. Nakao, William J. Shufesky, Amanda L. Williams, Rishab Humar, Rosemary A. Hoffman, Warren D. Shlomchik, Martin H. Oberbarnscheidt, Fadi G. Lakkis, Adrian E. Morelli

Research output: Contribution to journal › Article › peer-review

46 Citations (Scopus)

Abstract

Successful engraftment of organ transplants has traditionally relied on preventing the activation of recipient (host) T cells. Once T-cell activation has occurred, however, stalling the rejection process becomes increasingly difficult, leading to graft failure. Here we demonstrate that graft-infiltrating, recipient (host) dendritic cells (DCs) play a key role in driving the rejection of transplanted organs by activated (effector) T cells. We show that donor DCs that accompany heart or kidney grafts are rapidly replaced by recipient DCs. The DCs originate from non-classical monocytes and form stable, cognate interactions with effector T cells in the graft. Eliminating recipient DCs reduces the proliferation and survival of graft-infiltrating T cells and abrogates ongoing rejection or rejection mediated by transferred effector T cells. Therefore, host DCs that infiltrate transplanted organs sustain the alloimmune response after T-cell activation has already occurred. Targeting these cells provides a means for preventing or treating rejection.

Original language	English
Article number	12623
Journal	Nature communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms12623
Publication status	Published - Aug 24 2016
Externally published	Yes

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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10.1038/ncomms12623

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Zhuang, Q., Liu, Q., Divito, S. J., Zeng, Q., Yatim, K. M., Hughes, A. D., Rojas-Canales, D. M., Nakao, A., Shufesky, W. J., Williams, A. L., Humar, R., Hoffman, R. A., Shlomchik, W. D., Oberbarnscheidt, M. H., Lakkis, F. G., & Morelli, A. E. (2016). Graft-infiltrating host dendritic cells play a key role in organ transplant rejection. Nature communications, 7, [12623]. https://doi.org/10.1038/ncomms12623

Graft-infiltrating host dendritic cells play a key role in organ transplant rejection. / Zhuang, Quan; Liu, Quan; Divito, Sherrie J.; Zeng, Qiang; Yatim, Karim M.; Hughes, Andrew D.; Rojas-Canales, Darling M.; Nakao, A.; Shufesky, William J.; Williams, Amanda L.; Humar, Rishab; Hoffman, Rosemary A.; Shlomchik, Warren D.; Oberbarnscheidt, Martin H.; Lakkis, Fadi G.; Morelli, Adrian E.

In: Nature communications, Vol. 7, 12623, 24.08.2016.

Research output: Contribution to journal › Article › peer-review

Zhuang, Q, Liu, Q, Divito, SJ, Zeng, Q, Yatim, KM, Hughes, AD, Rojas-Canales, DM, Nakao, A, Shufesky, WJ, Williams, AL, Humar, R, Hoffman, RA, Shlomchik, WD, Oberbarnscheidt, MH, Lakkis, FG & Morelli, AE 2016, 'Graft-infiltrating host dendritic cells play a key role in organ transplant rejection', Nature communications, vol. 7, 12623. https://doi.org/10.1038/ncomms12623

Zhuang, Quan ; Liu, Quan ; Divito, Sherrie J. ; Zeng, Qiang ; Yatim, Karim M. ; Hughes, Andrew D. ; Rojas-Canales, Darling M. ; Nakao, A. ; Shufesky, William J. ; Williams, Amanda L. ; Humar, Rishab ; Hoffman, Rosemary A. ; Shlomchik, Warren D. ; Oberbarnscheidt, Martin H. ; Lakkis, Fadi G. ; Morelli, Adrian E. / Graft-infiltrating host dendritic cells play a key role in organ transplant rejection. In: Nature communications. 2016 ; Vol. 7.

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abstract = "Successful engraftment of organ transplants has traditionally relied on preventing the activation of recipient (host) T cells. Once T-cell activation has occurred, however, stalling the rejection process becomes increasingly difficult, leading to graft failure. Here we demonstrate that graft-infiltrating, recipient (host) dendritic cells (DCs) play a key role in driving the rejection of transplanted organs by activated (effector) T cells. We show that donor DCs that accompany heart or kidney grafts are rapidly replaced by recipient DCs. The DCs originate from non-classical monocytes and form stable, cognate interactions with effector T cells in the graft. Eliminating recipient DCs reduces the proliferation and survival of graft-infiltrating T cells and abrogates ongoing rejection or rejection mediated by transferred effector T cells. Therefore, host DCs that infiltrate transplanted organs sustain the alloimmune response after T-cell activation has already occurred. Targeting these cells provides a means for preventing or treating rejection.",

author = "Quan Zhuang and Quan Liu and Divito, {Sherrie J.} and Qiang Zeng and Yatim, {Karim M.} and Hughes, {Andrew D.} and Rojas-Canales, {Darling M.} and A. Nakao and Shufesky, {William J.} and Williams, {Amanda L.} and Rishab Humar and Hoffman, {Rosemary A.} and Shlomchik, {Warren D.} and Oberbarnscheidt, {Martin H.} and Lakkis, {Fadi G.} and Morelli, {Adrian E.}",

note = "Funding Information: This work was supported by grants from the US National Institutes of Health (R01 AI049466 and R01 AI099465 to F.G.L., and R01 HL130191 to A.E.M.); American Society of Nephrology (Merrill Grant in Transplantation to MHO and Donald E. Wesson Research Fellowship to KMY); American Heart Association (14GRNT19810000 to A.E.M.); the National Natural Science Foundation of China NSFC81401318 (to Q.L.) and the Frank and Athena Sarris Chair in Transplantation Biology to F.G.L.",

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AU - Nakao, A.

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AU - Humar, Rishab

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AU - Shlomchik, Warren D.

AU - Oberbarnscheidt, Martin H.

AU - Lakkis, Fadi G.

AU - Morelli, Adrian E.

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N2 - Successful engraftment of organ transplants has traditionally relied on preventing the activation of recipient (host) T cells. Once T-cell activation has occurred, however, stalling the rejection process becomes increasingly difficult, leading to graft failure. Here we demonstrate that graft-infiltrating, recipient (host) dendritic cells (DCs) play a key role in driving the rejection of transplanted organs by activated (effector) T cells. We show that donor DCs that accompany heart or kidney grafts are rapidly replaced by recipient DCs. The DCs originate from non-classical monocytes and form stable, cognate interactions with effector T cells in the graft. Eliminating recipient DCs reduces the proliferation and survival of graft-infiltrating T cells and abrogates ongoing rejection or rejection mediated by transferred effector T cells. Therefore, host DCs that infiltrate transplanted organs sustain the alloimmune response after T-cell activation has already occurred. Targeting these cells provides a means for preventing or treating rejection.

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