Research ArticleTransplantation

Host Alloreactive Memory T Cells Influence Tolerance to Kidney Allografts in Nonhuman Primates

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Science Translational Medicine  08 Jun 2011:
Vol. 3, Issue 86, pp. 86ra51
DOI: 10.1126/scitranslmed.3002093

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The Slippery Slope of Transplantation Tolerance

Although science is respected as an impartial pursuit, even the most unbiased observer must begin with assumptions to design experiments. But even seemingly reasonable hypotheses don’t always survive experimental scrutiny. Transplantation researchers began with the credible assumption that laboratory mice can serve as a model for human transplantation. Thus, when scientists showed that mice can accept human grafts without life-long immunosuppression, researchers enthusiastically attempted to translate these findings to nonhuman primates and patients—to no avail. Nadazdin et al. now provide a potential explanation for this discrepancy—a pre-existing pool of graft-reactive memory T cells.

Memory T cells respond more rapidly and with greater strength than other T cells that have not previously seen a specific antigen. As the name suggests, memory T cells are long-lived in patients and explain in part the success of vaccination in preventing subsequent infections. Laboratory mice lack large numbers of memory T cells because they live in germ-free conditions, unlike people who, despite their best efforts, do not. This lifestyle difference was not thought to be a problem for transplantation studies, because people have not been previously exposed to donor-derived alloantigens and thus were not expected to have a memory response. In an unexpected twist, primates have been shown to have a relatively high frequency of alloreactive memory T cells before transplantation, perhaps as a result of cross-reactivity from previous infections.

Nadazdin et al. now investigate the effects of these preexisting alloreactive memory T cells on transplant tolerance in nonhuman primates. The authors found that transplanted organs are rejected from monkeys with high numbers of preexisting alloreactive memory T cells, but survive long-term in monkeys with low numbers of these cells. Indeed, the animals with low numbers of alloreactive memory cells were rendered tolerant to the transplanted kidney, which was not rejected despite a lack of continued immunosuppression. This tolerance was allospecific, because both tolerant and rejecting monkeys had similar levels of homeostatic memory T cell expansion, but only rejecting monkeys displayed expanded levels of donor-reactive memory T cells after transplantation. These findings suggest two approaches to improving tolerance induction in transplant patients: One could either pair grafts with patients who have low numbers of donor-specific memory T cells or devise a way to eliminate these memory T cells from patients before transplantation. In this case, questioning assumptions did not validate the assumption, but instead yielded new information that may help researchers overcome barriers to transplant tolerance.

Footnotes

  • Citation: O. Nadazdin, S. Boskovic, T. Murakami, G. Tocco, R.-N. Smith, R. B. Colvin, D. H. Sachs, J. Allan, J. C. Madsen, T. Kawai, A. B. Cosimi, G. Benichou, Host Alloreactive Memory T Cells Influence Tolerance to Kidney Allografts in Nonhuman Primates. Sci. Transl. Med. 3, 86ra51 (2011).

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