Académie royale de Médecine de Belgique

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Abdul Rao (USA)

(Séance du 28 octobre 2000)

INCREASED CHIMERISM AND TOLERANCE IN HUMANS

par Abdul S. RAO, Directeur de la Section de transplantation cellulaire (Institut Thomas E. Starl de transplantation – USA).

The persistence of donor leukocytes (i.e. chimerism) in the tissues of long-term functioning organ allograft recipients prompted us to conclude that these cells may play a seminal role in graft acceptance.  This hypothesis is supported by the observation that similar to that to microorganisms, rejection or acceptance (tolerance) of transplanted allografts may be governed by the migration and localization of the antigen.  Given that these migratory cells are of donor BM origin, we reasoned that their adjuvant perioperative infusion into organ allograft recipients would enhance this phenomenon.  As a consequence, since 1992, 254 primary allograft recipients have received peri-operative infusion of a single dose of 3-6x108  unmodified donor BMCells/kg body weight.  The mean recipient and donor age was 40.7 and 30.4 years respectively, with follow-up ranging from 3-2574 d.  Additionally, since April 1996, we have also accrued 57 organ recipients into a concurrent protocol involving multiple (three) sequential perioperative infusion of unmodified BM (2x108 cells/kg/d) from dO-2 post-transplantation; the mean recipient age and donor age was 45,7 and 33,6 years respectively with a follow-up ranging from 4-1341 d. Organ recipients (n = 186) for whom BM was not available were monitored as controls.  Immunosuppression was with tacrolimus and steroids.  Cellcept being administered to 133 study and 76 control patients.  In addition to serial monitoring of clinical parameters, the presence of donor cell chimerism (by flow cytometry and PCR) and cellular immune responses by (MLR) were also ascertained using recipient’s peripheral blood.  The infusion of BM was safe and except for 70 (22,5 %), all study patients have optima graft function; none being lost to causes uniquely ascribed to ancillary BM infusion.  Of the control patients, allografts in 45 (24,2 %) have been lost during the course of follow-up.  A slightly higher incidence of mild to moderate acute cellular rejection (ACR) was witnessed in the control (70 %) patients as compared to that to the study (64 %).  This salutary effect of adjuvant BM infusion was perhaps most discerned in the heart recipients in whom 62 % of the study patients (as compared to 18 % of the controls) were free of rejection (Grade 3A or highter) in the first six months post-TX (p=0.006, Fisher’s exact test).  The incidence of obliterative bronchiolitis was also statistically lower in study lung patients (1/26;3.8 %) as compared to the contemporaneously acquired controls (4/13; 31 %).  Among those at least one year post-TX, a slightly higher incidence of steroid-free existence has been achieved in the BM-augmented (57 %) of BM-augmented liver, lung and kidney recipients, as compared to that to control (44 %).  Interestingly, a much lower incidence of DSH was evidenced in the study and control heart and kidney+pancreas transplant recipients.  In conclusion, higher level of chimerism and DSH is achieved in BM-augmented patients as compared to controls.  The beneficial effect of this finding was evidenced by markedly lowered incidence of ACR and chronic rejection in study patients.     

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