Tolerance to musculoskeletal allografts with transient lymphocyte chimerism in miniature swine.

BACKGROUND: Although transplantation of musculoskeletal allografts in humans is technically feasible, the adverse effects of long-term immunosuppression subject the patient to high risks for correcting a non-life-threatening condition. Achieving immunologic tolerance to musculoskeletal allografts, without the need for chronic immunosuppression, could expand the clinical application of limb tissue allografting. Tolerance to musculoskeletal allografts has been accomplished previously in miniature swine in our laboratory. Although stable, mixed chimerism has been suggested as the mechanism underlying long-term tolerance in a rat limb model, the mechanism of this tolerance induction has not been established. This report explores the possible relationship between hematopoietic chimerism and tolerance to musculoskeletal allografts in swine. METHODS: Twelve miniature swine underwent vascularized musculoskeletal allograft transplantation from histocompatibility complex (MHC) matched, minor antigen-mismatched donors. Eight animals received a 12-day coprse of cyclosporine, one of which was excluded due to subtherapeutic levels. Four recipients were not immunosuppressed. Serial biopsies to assess graft viability and flow cytometry to assess chimerism were performed. Donor and third-party skin grafts were placed on recipients with surviving allografts greater than 100 days to validate tolerance. RESULTS: Both groups developed early peripheral chimerism, but this chimerism became undetectable by postoperative day 19 in the cyclosporine group and by day 13 in the control group. Animals receiving cyclosporine developed permanent tolerance to their allografts, whereas those not receiving cyclosporine rejected their allografts in 6-9 weeks. Animals demonstrating tolerance to their bone allografts also demonstrated prolonged donor skin graft survival. CONCLUSIONS: Induction of tolerance to musculoskeletal allografts can be achieved in the MHC matched swine. Although hematopoietic chimerism is present in the immediate postoperative period, persistent, long-term chimerism does not seem to be necessary for maintenance of such tolerance.

Tolerance to limb tissue allografts between swine matched for major histocompatibility complex antigens.

Transplantation of limb tissue allografts would greatly expand the realm of reconstructive surgery. However, the toxicity of chronic immunosuppression has adversely tilted the risk-benefit balance for clinical transplant. In this study, a procedure was sought to achieve host tolerance to limb tissue allografts through matching of the major histocompatibility complex (MHC) antigens between donor and host swine using only a 12-day course of cyclosporine. Massachusetts General Hospital (MGH) miniature swine were used as a large animal model with defined MHC, and musculoskeletal grafts from the donor hind limb were transplanted heterotopically to the recipient femoral vessels. Allografts from MHC-mismatched donors treated with cyclosporine (n = 4) were rejected in less than 6 weeks by gross inspection and histologic sections. Allografts from MHC-matched, minor antigen mismatched donors not treated with cyclosporine (n = 4) were rejected between 9 and 12 weeks. Allografts from similarly matched donors treated with 12 days of cyclosporine (n = 7) showed no evidence of rejection until sacrifice between 25 and 47 weeks. Thus allograft tolerance was achieved between MHC-matched swine using a limited course of cyclosporine. Demonstration of limb tissue allograft survival in a large animal model without long-term immunosuppression represents an important step toward clinical transplantation.

Comparing preincisional with postincisional bupivacaine infiltration in the management of postoperative pain.

OBJECTIVE: To determine if preemptive local anesthesia yields better postoperative pain control than infiltration of local anesthetic at the time of wound closure. DESIGN: Prospective, randomized trial. SETTING: Private community teaching hospital. PATIENTS: Two-hundred consecutive patients undergoing elective laparotomy were enrolled in the study between September 1993 and April 1995. Eighty-eight patients were excluded from the study for violation of protocol, leaving a total of 112 patients to be evaluated. Patients were divided into 2 groups: preincisional (n = 52) and postincisional (n = 60). INTERVENTIONS: Patients in the preincisional group received 40 mL of 0.25% bupivacaine (Marcaine) 5 minutes before the incision; patients in the postincisional group received 40 mL of 0.25% bupivacaine immediately after approximation of the fascia and before closure of the skin. MAIN OUTCOME MEASURES: The control of the long-term (3-day) postoperative pain in relationship to timing of local anesthetic given. RESULTS: Study groups were comparable for age, weight, sex, operative time, and length of incision. No significant difference in the amount of morphine used or subjective evaluation of pain was noted between the preincisional and the postincisional groups. CONCLUSIONS: Based on the theory of "dorsal horn hypersensitivity," several clinical trials have shown significant improvement in pain control with preincisional infiltration of local anesthetic. Our results indicate that pain was no better controlled with preincisional infiltration than with postincisional infiltration of bupivacaine, raising the question of the benefit of preemptive anesthesia at the local level in long-term postoperative care.