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


METHODS
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).


CONCLUSIONS
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.
Department of Surgery, Harvard Medical School, Massachusetts General Hospital, Boston 02114, USA.
T
T
Kawai
S L
SL
Wee
H
H
Bazin
D
D
Latinne
J
J
Phelan
S
S
Boskovic
D S
DS
Ko
H Z
HZ
Hong
S
S
Mauiyyedi
O
O
Nadazdin
G
G
Abrahamian
F
F
Preffer
R B
RB
Colvin
D H
DH
Sachs
A B
AB
Cosimi
D000818:Animals; D002469:Cell Separation; D007108:Immune Tolerance; D016030:Kidney Transplantation / Q000276:immunology; D007694:Killer Cells, Natural / Q000166:cytology* / Q000502:physiology; D008252:Macaca fascicularis / Q000235:genetics*; D008297:Male; D018183:Transplantation Chimera; D019172:Transplantation Conditioning