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Summer 1996Volume 3, Number 1 |
Long-term use of immunosuppressive drugs results in substantial infectious and toxic morbidity for recipients of organ allografts. Numerous approaches have been evaluated in an effort to induce tolerance in these patients, so that immunosuppressive therapy can be discontinued. Until now, none has proved successful. A number of investigators are currently looking at innovative strategies using the donor immune system to induce tolerance, and these trials were the focus of several sessions at the 15th Annual Meeting of the American Society of Transplant Physicians held in Dallas in May.
It has only recently become apparent that lymphohematopoietic mixed chimerism in solid organ transplant recipients could be detected in the peripheral blood posttransplant. Mixed chimerism probably results from passive transfer of mature cells and progenitor cells of the lymphoid and hematopoietic lineages. The effect on transplant outcome has been unclear. Several clinical reports underscored the importance of this phenomenon.
McSherry and colleagues from the University of Minnesota evaluated peripheral blood microchimerism using the polymerase chain reaction in lung allograft recipients and correlated the findings with clinical parameters monitored for 3-48 months posttransplant. They found a direct correlation between microchimerism and pulmonary function. Specifically, the FEV1 rose and fell in parallel with the degree of microchimerism.
Yussim and others from Israel reported on microchimerism in renal allograft recipients. In a series of 20 patients with a two-year mean follow-up, these investigators found that donor-specific hyporesponsiveness in vitro correlated inversely with peripheral blood microchimerism. Patients with microchimerism had better renal function and were also less likely to experience rejection episodes during the follow-up period.
These results encouraged others to evaluate active transfer of donor lymphohematopoietic cells to improve transplant outcome. It has long been known that tolerance is in fact induced in allogeneic marrow transplant recipients, and long-term immunosuppression is not necessary for these patients. With this information in mind, several centers have initiated trials of combined marrow and solid organ allograft transplantation.
At the Pittsburgh Transplantation Institute (PTI), Dr. Thomas Starzl and his collaborators have administered donor marrow to liver allograft recipients during the perioperative period. The number of cells infused was 3-5×108/kg. This is the same cell dose as is used for a standard allogeneic marrow transplant, but the liver allograft recipients did not receive any myeloablative therapy prior to transplantation.
At the PTI, Rao and others monitored clinical outcome and microchimerism in the marrow-augmented liver allograft recipients and in a contemporaneous control group. Acute graft-versus-host disease (GVHD) occurred in two patients in the study group, and required treatment with steroids in only one. Chimerism was detected in the peripheral blood of all study patients and in 50% of the control group. The study patients also had a higher incidence of donor-specific hyporesponsiveness in vitro, and a slight decrease in the incidence of rejection. Donor-specific immunomodulation was also confirmed by Zeevi and others from the PTI for renal, cardiac, and lung allograft recipients who had received donor marrow.
| It has only recently become apparent that lymphohematopoietic mixed chimerism in solid organ transplant recipients could be detected in the peripheral blood posttransplant. Mixed chimerism probably results from passive transfer of mature cells and progenitor cells of the lymphoid and hematopoietic lineages. The effect on transplant outcome has been unclear. |
Many investigators have suggested that the timing of marrow infusion might be important. Using a rat cardiac allograft model, Padberg from the University of Giessen found that the day of donor marrow infusion altered outcome substantially. These investigators noted that cyclosporine and donor marrow had a synergistic effect, and that allograft survival was longest when donor marrow was infused on postoperative day 6.
The issue of timing of donor marrow infusion in the clinical setting was investigated by Ricordi at the University of Miami. This group administered donor marrow perioperatively or on various days postoperatively to patients undergoing liver transplantation and compared the outcomes to controls not receiving donor marrow. The best outcome was achieved in the group given donor marrow on postoperative days 5 and 11. For this group, the incidence of rejection was reduced (18% vs 38%) and fewer liver allograft failures occurred (0/22 vs 7/85).
These results suggested that donor marrow infusion with resulting active induction of chimerism could be beneficial in organ transplantation. However, all investigators cautioned that this strategy cannot be considered standard therapy at this time. Ongoing investigations include identification of the cell subset responsible for tolerance induction and maintenance, modification of the donor marrow to reduce the risk of GVHD, use of nontoxic myelosuppressive drugs that might increase the degree of chimerism, and determination of the appropriate number of donor marrow cells as well as the optimal day of infusion. The initial results in this area, however, are certainly encouraging.
Donna Przepiorka, MD, PhD
Section of Bone Marrow Transplantation
M.D. Anderson Cancer Center
Houston, Texas
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