Association of natural killer cell depletion with induction of mixed chimerism and allograft tolerance in non-human primates

Tatsuo Kawai, Siew Lin Wee, Herve Bazin, Dominique Latinne, Joanne Phelan, Svetlan Boskovic, Dicken S.C. Ko, Han Zhou Hong, Shamila Mauiyyedi, Ognjenka Nadazdin, Gregory Abrahamian, Frederic Preffer, Robert B. Colvin, David H. Sachs, A. Benedict Cosimi

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35 Scopus citations

Abstract

Background. Nonmyeloablative T cell depletion followed by donor bone marrow infusion has proved to be an effective approach to induction of mixed chimerism and tolerance of organ allografts in non-human primates. To help define the mechanisms involved we have compared T cell depletion with ATG versus anti-CD2 monoclonal antibody with respect to establishment of mixed chimerism and induction of tolerance. Method: Both nonmyeloablative regimens included low dose total body irradiation (1.5 Gy x 2), thymic irradiation (7 Gy), splenectomy and kidney plus donor bone marrow transplantation, followed by a 4-week posttransplant course of cyclosporine. In addition, the ATG group (13 recipients) received antithymocyte globulin, although the LOCD2b group (10 recipients) were treated with an anti-CD2 monoclonal antibody (LOCD2b). Results. In the ATG group, 11 of 13 monkeys developed multilineage chimerism and 9 survived for more than 100 days without kidney allograft rejection. In contrast, 0/10 monkeys in the LOCD2b group developed chimerism, 5 died of infection and 5 suffered progressive rejection; only 1 recipient survived beyond 100 days. Sequential monitoring of peripheral blood mononuclear cells revealed greater T cell (CD3+) depletion in the LOCD2b-treated animals compared to those receiving ATG. However, NK cells (CD16+CD8+) were significantly more depleted in the ATG group and NK function remained abrogated longer after ATG than LOCD2b treatment (3 weeks vs. <5 days). Conclusion: Despite excellent T cell depletion by LoCD2b, ATG was more effective in inducing chimerism and tolerance. This difference correlated with anti-NK activity of the two reagents. These data suggest that NK cells may also resist engraftment of allogeneic bone marrow cells in this model.

Original languageEnglish (US)
Pages (from-to)368-374
Number of pages7
JournalTransplantation
Volume70
Issue number2
DOIs
Publication statusPublished - Jul 27 2000

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ASJC Scopus subject areas

  • Transplantation

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