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Homeostatic proliferation is a barrier to transplantation tolerance

Nature Medicine volume 10, pages 87–92 (2004)Cite this article

Abstract

Despite the ease of inhibiting immune responses by blockade of T-cell costimulation in naive rodent models, it is difficult to suppress those responses in animals with memory cells1,2. Studies demonstrating the importance of alloreactive T-cell deletion during tolerance induction have promoted use of peritransplant T-cell-depleting therapies in clinical trials3,4,5,6. But potentially complicating wide-scale, nonspecific T-cell depletion is the finding that extensive T-cell proliferation can occur under conditions of lymphopenia. This process, termed homeostatic proliferation7,8, may induce acquisition of functional memory T cells9,10,11,12,13. Here, using clinically relevant mouse models of peripheral T-cell depletion, we show that residual nondepleted T cells undergo substantial homeostatic expansion. In this setting, costimulatory blockade neither significantly suppresses homeostatic proliferation nor prevents allograft rejection. In addition, T cells that have completed homeostatic proliferation show dominant resistance to tolerance when adoptively transferred into wild-type recipients, consistent with known properties of memory cells in vivo. These findings establish the importance of homeostatic proliferation in clinically relevant settings, demonstrate the barrier that homeostatic proliferation can present to the induction of transplantation tolerance, and have important implications for transplantation protocols that use partial or complete peripheral T-cell depletion.

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Figure 1: Homeostatic proliferation after partial T-cell depletion.
Figure 2: Homeostatic proliferation induces resistance to tolerance induction by costimulatory blockade.
Figure 3: Kinetics of homeostatic proliferation and long-term effect on function and tolerance induction.
Figure 4: Tolerance resistance in wild-type mice.

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Acknowledgements

We thank T. Laufer, F. Lakkis, T. Strom, M. Sykes, D. Sachs, H. Petrie and J. Bluestone for helpful discussions; A. Wells for critical review of the manuscript; and T. Gray for expert animal care. This work was supported by National Institutes of Health grants AI-37691 (L.A.T.), AI-41521 (M.H.S. and L.A.T.) and AI-43626 (L.A.T.).

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  1. Zihao Wu and Steven J Bensinger: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medicine, University of Pennsylvania, Philadelphia, 19104, Philadelphia, USA

    Zihao Wu, Steven J Bensinger, Jidong Zhang, Chuangqi Chen & Laurence A Turka

  2. Department of Medicine, Brigham and Women's Hospital, Boston, 02131, Massachusetts, USA

    Xueli Yuan & Mohamed H Sayegh

  3. Department of Surgery, University of Pennsylvania, Philadelphia, 19104, Pennsylvania, USA

    Xiaolun Huang, James F Markmann & Bruce R Rosengard

  4. Department of Radiation Oncology, University of Pennsylvania, Philadelphia, 19104, Pennsylvania, USA

    Alireza Kassaee

  5. Pathology and Biesecker Pediatric Liver Center, Children's Hospital of Philadelphia, Philadelphia, 19104, Pennsylvania, USA

    Wayne W Hancock

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Correspondence to Laurence A Turka.

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Wu, Z., Bensinger, S., Zhang, J. et al. Homeostatic proliferation is a barrier to transplantation tolerance. Nat Med 10, 87–92 (2004). https://doi.org/10.1038/nm965

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