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Combined Antagonism Of Early Inflammatory Pathways Does Not Prevent Acute Rejectionin Vascularized Composite Allotransplantation (vca)
Majid Rezaei, DDS MSc, Carlos Ordenana, MD, Vahe Fahradyan, MD, Robert Fairchild, PhD, William Baldwin, MD, PhD, Danielle Kish, PhD, Francis Papay, MD, Antonio Rampazzo, MD, PhD, Bahar Bassiri Gharb, MD, PhD.
Cleveland Clinic Foundation, Cleveland, OH, USA.

Purpose:
Long-term immunosuppression, necessary to prevent rejection of vascularized composite allografts, is associated with systemic side effects, such as drug toxicity, opportunistic infections, and malignancy. Antagonism of Anti-Tumor Necrosis Factor, anti-CD40 Ligand monoclonal antibodies and Lymphocyte Function Associated Antigen 1 (LFA-1) has shown to prolong the survival of heart allografts up to 100 days.. Blockade of CD-40/CD40L pathway decreases cytotoxic lymphocyte response, down-regulates the B-cell pathways and decreases cytokine production such as TNF-α. (LFA-1) is critical for T cell arrest on the vascular endothelium and activation of CD4 and CD8 T cells. TNF- α is a mediator of ischemia-reperfusion injury and its increased systemic levels has been detected during acute rejection episodes. The goal of this study was to characterize the efficacy of combined antibody suppression in preventing acute rejection in a rat hindlimb transplant model.
Methods:
Twelve hindlimb transplants were performed from ACI donors to Lewis recipients. Animals in the control group (n=6) received Tacrolimus (1mg/kg), Mycophenolate (20mg/kg) and Methylprednisolone sodium succinate (0.5mg/kg) daily for 100 days. In the experimental group (n=6), Anti-LFA1 (10mg/kg) was given on the day before surgery. On transplantation day, anti-TNF (10mg/kg) and anti-CD40L (16mg/kg) were administered. On post-operative day 1, all three antibodies were given.
Results:
The average survival rate for the control group was 8127 days. On average, the animals lost 23% of their initial weights. Three animals survived until the end point of the study. Three animals died for failure to thrive and development of gastrointestinal tumors. In the experimental group, all animals presented acute rejection with complete necrosis of the allograft within an average of 82 days. The survival rates of the 2 groups were significantly different (p<0.001). Histology of the skin and muscle samples in the control group showed normal epidermis, dermis and muscular tissue, while the experimental group displayed necrosis of the epidermis and massive inflammation of underlying dermis and muscle.
Conclusion:
Our results showed that the triple antibody regimen alone would not prevent acute rejection in this model of VCA. This strategy does not seem strong enough to prevent the immediate response of the immune system. The efficacy of the combined antibody treatment following induction with conventional agents has to be investigated yet.


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