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.
Kawai
T
T
Department of Surgery, Harvard Medical School, Massachusetts General Hospital, Boston 02114, USA.
Wee
S L
SL
Bazin
H
H
Latinne
D
D
Phelan
J
J
Boskovic
S
S
Ko
D S
DS
Hong
H Z
HZ
Mauiyyedi
S
S
Nadazdin
O
O
Abrahamian
G
G
Preffer
F
F
Colvin
R B
RB
Sachs
D H
DH
Cosimi
A B
AB
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