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Challenges of Triple Immunosuppression in Non-Human Primate Models of Vascularized Composite Allotransplantation
Zhi Yang Ng, MD, David A. Leonard, MBChB, MRCS, PhD, Matthew W. Defazio, BS, Zachary W. Heroux, BS, Josef M. Kurtz, PhD, Curtis L. Cetrulo, Jr., MD, FACS, FAAP.
Massachusetts General Hospital, Boston, MA, USA.

PURPOSE:
Tolerance of renal and lung allografts in non-human primates (NHPs) has been achieved by bone marrow transplantation (BMT) 4 months after solid organ transplant (SOT) and recipients receive triple immunosuppression (FK506, MMF, methylprednisolone) in the interim. This delayed tolerance induction protocol (DTIP) has been adopted in NHP VCA studies. We report the challenges of triple immunosuppression during the 4-month delay.
METHODS:
To prevent acute rejection, NHPs received induction therapy (anti-thymocyte globulin) pre-VCA. Post-VCA, NHPs were maintained on triple immunosuppression and followed closely with serial biopsies (of VCA and host skin) and immunologic assays; further biopsies were performed in suspected acute rejection.
RESULTS:
Post-VCA, acute rejection (1 to 3 episodes, between 1 and 3 months) (Figures 1 and 2) and other complications (Table 1) coincided with the near complete turnover of skin resident leukocytes (by flow cytometric analysis) in the VCA to recipient-origin cells by POD 30 (Figure 3). In all recipients, there was no evidence of donor-specific antibodies or in vitro donor responses.
CONCLUSION:
Unlike SOT, triple immunosuppression may not be sufficient for VCA during the original 4-month delay in the DTIP. Acute rejection likely developed when immunosuppression levels fluctuated; the overall immunosuppressive load led to systemic complications necessitating euthanasia. Further studies with a shortened delay period and overall duration of immunosuppression are underway for earlier BMT and tolerance induction.
Results of NHPs on 4-Months Triple Immunosuppression
RecipientVCAMHC-MismatchComplication(s)Allo-AntibodyAnti-Donor ResponseSurvival
M1413Orthotopic Upper ExtremityFullAcute rejection
(POD 90)
Weight loss
NoNo> 120
Reached BMT
M4213Orthotopic Upper ExtremityFullAcute rejection
(POD 30)
NoNo51*
M6014Heterotopic Partial FaceFullAcute rejection
(POD 28, 48, 60)
Weight loss (PTLD)
NoNo107^
M6714Heterotopic Partial FaceHaploidenticalWeight loss (PTLD)NoNo79^
*Biopsy proven acute rejection developed on POD 30 and progressed to irreversible VCA loss despite two attempts at steroid boluses, leading to euthanization on POD 51
^Euthanized due to post-transplant lymphoproliferative disorder (PTLD)


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