Bone marrow augmentation in kidney transplantation: a large animal study |
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Authors: | R W G Gruessner Kristine Y Zhang Michele Dunning Raouf E Nakhleh Angelika C Gruessner |
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Institution: | (1) Department of Surgery, University of Minnesota, Mayo Mail Code 90, 420 Delaware St. SE, Minneapolis, MN 55455, USA Tel.: + 1-6 12-6 25 14 85 Fax: + 1-6 12-6 24 71 68, US |
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Abstract: | Specific immunomodulatory strategies are required to eliminate the need for lifelong dependence on debilitating immunosuppressants.
One proposed strategy is to simultaneously transplant the kidney and infuse donor-specific bone marrow cells. We prospectively
studied the effect of unmodified donor-specific bone marrow infusion (DSBMI) on rejection, infection, graft-versus-host disease (GvHD), and graft survival.
We performed 57 kidney transplants in mixed lymphocyte culture (MLC)-reactive, outbred pigs. The groups of recipient pigs
differed according to the use of (1) indefinite versus short-term tacrolimus-based immunosuppression, (2) DSBMI, and (3) recipient
preconditioning (RPC: whole body irradiation with 400 rads on day 0 and horse anti-pig thymocyte globulin (ATG) on days –2,
–1, and 0). In all, we studied eight groups: group 1, nonimmunosuppressed control pigs (n = 8); group 2, nonimmunosuppressed DSBMI pigs (n = 7); group 3, nonimmunosuppressed RPC + DSBMI pigs (n = 5); group 4, tacrolimus (indefinite) pigs (n = 11); group 5, tacrolimus (10 days only) pigs (n = 5); group 6, DSBMI + tacrolimus (indefinite) pigs (n = 8); group 7, DSBMI + tacrolimus (10 days only) pigs (n = 6); and group 8, RPC + DSBMI + tacrolimus (indefinite) pigs (n = 7). DSBMI alone (group 2) or in combination with RPC (group 3) did not prolong graft survival, as compared with nonimmunosuppressed
controls (group 1). In groups 1, 2, and 3, all but one pig died from rejection; in group 3 only, 45 % of the pigs died from
concurrent infection or GvHD, indicating that RPC in combination with DSBMI aggravated the risk of generalized infection and
GvHD. Post-transplant immunosuppression – irrespective of indefinite or short-term administration – was required for prolonged
graft survival. With indefinite use of immunosuppression, graft survival rates and death rates from rejection were not different
for pigs with (group 6) versus without (group 4) DSBMI; however, the death rate from infection was higher in group 6, suggesting
that the bone marrow inoculum increased the risk of systemic infection. With short-term use of immunosuppression, graft survival
rates were higher and death rates from rejection lower for pigs with (group 7) versus without (group 5) DSBMI. But DSBMI and
short-term immunosuppression (group 7) failed to prolong survival beyond that achieved with indefinite immunosuppression (groups
4 and 6). Although the combination of DSBMI and short-term immunosuppression (group 7) reduced the risk of infection, it did
not avert severe rejection. The addition of RPC to DSBMI and indefinite immunosuppression (group 8) significantly decreased
graft survival, as compared with groups 4, 6, and 7. It also increased the incidence of death from rejection, GvHD, and infection,
or a combination thereof. Unmodified DSBMI did not prolong graft survival after kidney transplantation, nor did it decrease
the incidence of rejection. But it aggravated the risk of GvHD and infection. Short-term immunosuppression with DSBMI reduced
the incidence of death from infection or GvHD, but it resulted in a higher incidence of death from rejection (as compared
with indefinite use of immunosuppression). RPC, combined with DSBMI and indefinite immunosuppression, increased the death
rate from rejection, GvHD, infection, or a combination thereof. In this large animal study, the effect of unmodified DSBMI
has been disappointing. The search continues for the optimal way to successfully perform bone marrow augmentation in solid
organ transplants.
Received: 6 June 2000 Accepted: 28 December 2000 |
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Keywords: | Kidney transplantation Bone marrow augmentation Donor cell augmentation |
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