The role of C4d and donor specific antibodies in face and hand transplantation-a systematic review

Abstract

To date, little is known about the mechanisms of rejection in vascularized composite allotransplantation, particularly for antibody mediated rejection. Additionally, no clear guidelines exist for the diagnosis and management of antibody-mediated rejection in vascularized composite allotransplantation. A systematic review of electronic databases (Embase and PubMed) was conducted to evaluate the relationship of donor specific antibodies and C4d deposition in correlation with cellular rejection following hand and face transplantation reported by centers between 1998 and July 2023. We extracted data on serum donor specific antibodies at the time of biopsy proven rejection according to Banff classification and C4d staining of target tissues. Mann-Whitney U tests were performed to compare rejection grade between groups divided by status of C4d deposition and serum donor specific antibodies, and Fisher's Exact test was used to assess association between the two markers. This review adhered to PRISMA guidelines. A total of 26 patients (5 face, 21 hand) were identified and data on 90 acute rejection episodes with information on Banff grade, donor specific antibody status, and C4d deposition were available. Donor specific antibodies were found to be associated with higher rejection grade (p = 0.005). C4d was not found to be associated with higher rejection grade (p = 0.33). Finally, no significant association was found between concurrent status of the two markers (p = 0.23). These findings suggest that the presence of donor specifc antibodies may be associated with higher grades of acute cellular rejection following hand and face transplantation. More consistent reporting on rejection episodes is needed in order to better understand antibody-mediated rejection in vascularized composite allotransplantation.

Keywords: C4d; VCA; antibody-mediated rejection; donor specific antibody; reconstructive surgery; vascularized composite allotransplantation.

Figure 1

Preferred reporting items for systematic reviews and meta-analyses (PRISMA) flow diagram depicting systematic review and screening results.

Figure 2

Acute rejection episodes of hand and face transplants classified by banff 2007 rejection grade with C4d and DSA status. For hand and face transplants combined, mean rejection grade was found to be significantly higher in episodes reported positive for DSA (p = 0.005) but was not found to be different between episodes reported positive or negative for C4d (p = 0.33). Mean rejection grade was also not found to be significantly different based on status of either marker for isolated hand or face transplants (Hand Only: C4d; p = 0.42, DSA; p = 0.15, Face Only: C4d; p = 0.50, DSA; p = 0.61).

Figure 3

(A) ABMR is thought to primarily involve the graft endothelium and to be mediated by endothelial binding of anti-HLA antibodies (donor specific antibodies) against HLA surface molecules expressed on endothelium that lines donor vasculature. This can lead to a chronic inflammatory process ultimately leading to allograft vasculopathy (43). (B) In VCA, DSA may lower the threshold for homing of alloreactive T-cells, thereby promoting acute cellular rejection. This may be mediated by increased expression of leukocyte-endothelial cell interactions via ICAM1, VCAM1, and Sele (increased expression seen in suspected ABMR of VCA) (39). (Created with Biorender.com).