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Ann Thorac Surg 1995;60:1020
© 1995 The Society of Thoracic Surgeons
DR BRUCE A. REITZ (Stanford, CA): Doctor Pham should be congratulated for his presentation and Drs Griffith and Starzl for this very difficult clinical trial. They have demonstrated in their patients in these early results an increased incidence of microchimerism when compared with concurrent controls, and their hypothesis is that this chimerism will result in better long-term acceptance of the graft and perhaps a decrease in chronic rejection. Most previous work on bone marrow infusion at the time of transplantation has attempted to create donor-specific tolerance, perhaps an unacceptable or unobtainable clinical goal at the present time, but when bone marrow has been given it has usually been accompanied with some type of induction therapy, such as total lymphoid irradiation, whole body radiation, or antithymocyte globulin. My first question for Dr Pham is why induction therapy was not used in these patients. Even antithymocyte globulin alone would provide some induction, and antithymocyte globulin has been used as part of the lung transplant protocols at Pittsburgh in the past.
Second, Dr Pham, can you comment on how you might achieve a decrease in chronic rejection if there has been no significant decrease in the early rejection frequency or a significant increase in donor-specific hyporeactivity? I think your data show trends in this regard but the manuscript clearly shows that at this point there is no statistical difference.
Third, would you share with us some of the studies of FK 506 and donor bone marrow infusion and how this combination compares with cyclosporine in terms of chimerism induction?
Finally, the lack of graft-versus-host disease is very encouraging in this study, but I would give a word of caution in that in experiments that we have done with bone marrow infusion, the exact combination of accompanying immunosuppression is extremely important and minor changes can result in either hypersensitivity or, on the other hand, the induction of tolerance. So it is very important to have a very specific protocol and to follow it very closely. Doctor Pham, please comment on graft-versus-host disease in recipients of liver transplant and how those protocols might differ from your heart protocol.
Again, congratulations on what is a very difficult clinical study. We look forward next year or perhaps the year after to getting the long-term follow-up to see if your hypothesis has been validated.
DR JOHN R. BENFIELD (Sacramento, CA): While Dr Pham is coming to the microphone to respond to the questions, my sense of history allows me to comment that Dr David Blumenstock of Cooperstown, NY, and Dr Thomas of bone marrow transplant fame investigated the concept of chimerism as an adjunct to lung transplantation in inbred beagles almost 30 years ago.
DR PHAM: Thank you, Dr Reitz, for your comments. We did not use induction therapy such as antithymocyte globulin or radiation because we did not know what the antithymocyte globulin would do to the bone marrow stem cells. Doctor Barber and his associates from Birmingham, Alabama, had used antithymocyte globulin induction in their combined kidney-bone marrow trial and had observed an increase in the level of chimerism. However, their protocol was different from ours in that they had infused frozen bone marrow cells approximately 21 days after the patient had received a kidney transplant. We did not use preoperative radiation because of our concern for subjecting the patients to a higher risk of graft-versus-host-disease, and because of the difficult logistics due to the time constraint.
On your question about chronic rejection, the only available data on chimerism and chronic rejection are those reported by our group. We had shown that lung recipients with microchimerism had a lower risk of obliterative bronchiolitis development. These data form the basis for the current trial.
We have not used cyclosporine in recipients of combined bone marrow and heart or lung transplants. To date, we have not seen graft-versus-host disease in heart, lung, or kidney recipients who received concurrent bone marrow infusion. However, mild graft-versus-host disease developed in 2 of the 28 liver-bone marrow recipients. The graft-versus-host disease resolved spontaneously in 1, and with an increase in the prednisone dose from 7.5 mg/day to 15 mg/day in another.
Related Article
Ann. Thorac. Surg. 1995 60: 1015-1020.
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