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Composite Graft Pretreatment With Hydrogen Sulfide Delays the Onset of Acute Rejection

Fries, C. Anton, MA, FRCS(Plast)*†; Lawson, Sharon D., MD*; Wang, Lin C., MD*; Spencer, Jerry R., BS; Roth, Mark, MD§; Rickard, Rory F., PhD, FRCS(Plast); Gorantla, Vijay S., MD, PhD; Davis, Michael R., MD, FACS*‡

doi: 10.1097/SAP.0000000000001693
Transplantation Surgery and Research

Introduction Vascularized composite allotransplantation can reconstruct devastating tissue loss by replacing like-with-like tissues, most commonly in the form of hand or face transplantation. Unresolved technical and ethical challenges have meant that such transplants remain experimental treatments. The most significant barrier to expansion of this field is the requirement for systemic immunosuppression, its toxicity and effect on longevity.

Hydrogen sulfide (H2S) has been shown experimentally to ameliorate the ischemia reperfusion injury associated with composite tissue autotransplantation, which has been linked to acute rejection in solid organ transplantation. In this protocol, a large-animal model was used to evaluate the effect of H2S on acute rejection after composite tissue allotransplantation.

Materials and Methods A musculocutaneous flap model in SLA-mismatched swine was used to evaluate acute rejection of allotransplants in 2 groups: control animals (n = 8) and a treatment group in which the allografts were pretreated with hydrogen sulfide (n = 8). Neither group was treated with systemic immunosuppression. Acute rejection was graded clinically and histopathologically by an independent, blinded pathologist. Data were analyzed by t tests with correction for multiple comparisons by the Holm-Šídák method.

Results Clinically, H2S-treated tissue composites showed a delay in the onset of rejection that was statistically significant from postoperative day 6. Histopathologically, this difference between groups was also apparent, although evidence of a difference in groups disappeared beyond day 10.

Conclusions Targeted hydrogen sulfide treatment of vascularized composite allografts immediately before transplantation can delay acute rejection. This may, in turn, reduce or obviate the requirement for systemic immunosuppression.

From the *United States Army Institute of Surgical Research, San Antonio, TX;

Academic Department of Military Surgery and Trauma, Royal Centre for Defence Medicine, Birmingham, UK;

59MDW/Science and Technology, Joint Base, San Antonio, TX;

§Fred Hutchinson Cancer Research Center, Seattle, WA; and

University of Pittsburgh Medical Center, Pittsburgh, PA.

Received June 19, 2018, and accepted for publication, after revision September 20, 2018.

Conflicts of interest and sources of funding: This work was funded by the US Department of Defense and the United Kingdom Ministry of Defence. The proposal was funded through the US Air Force Medical Service Agency and coordinated through the 59MDW Office of Science and Technology.

The authors declare no conflict of interest.

The views expressed are those of the authors and do not reflect the official view or policy of the US Department of Defense, Department of the Army, Department of the Air Force or its Components, or the United Kingdom Ministry of Defence.

Reprints: C. Anton Fries, MA, FRCS(Plast), United States Army Institute of Surgical Research, Chambers Pass, Fort Sam Houston, San Antonio, TX 78234. E-mail:

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