Vascularized composite allotransplants as a mechanistic model for allograft rejection – an experimental study

Abstract

Summary Vascularized composite allotransplants (VCAs) seem to have several unique features of clinical and experimental importance, including uniquely definable lymphatic drainage that can be easily accessed at the level of ipsilateral regional node beds. Thus, VCA offers a unique opportunity to assess the relative contribution of peripheral and secondary lymphoid tissue to the process of rejection. We transplanted hind limb grafts from C3H donors to six different groups of C57BL/6 recipients: Spleen+Map3k14−/−; Spleen−Map3k14−/−; Spleen+Node−Map3k14−/−; and Spleen−Node−Map3k14−/−. As positive controls, we used Map3k14+/− with or without spleen. Map3k14+/− mice demonstrated an average graft survival of 9.6 and 9.2 days for Spleen− and Spleen+Map3k14+/−, respectively. Rejection in the Map3k14−/− group was considerably delayed (28.4 days, P = 0.002) in all recipients. The Spleen−Map3k14−/− mice rejected their hind limb allografts in an even more delayed fashion compared to Spleen+Map3k14−/− (54.4 days, P = 0.02). Histological analysis of skin showed that acute rejection in both Map3k14+/− mice groups was graded as Banff III or Banff IV. In the Map3k14−/− groups, rejection was graded as Banff III. We demonstrated that in the absence of lymph nodes, grafts reject in a delayed fashion. Also, splenectomy in alymphoplastic mice further extends graft survival, but does not eliminate rejection all together.

Cellular activation pathways and interaction networks in vascularized composite allotransplantation

“…Mounting body of evidence points toward CD8 + effector T cells as the hallmark effectors of VCA rejection targeting epidermal and follicular stem cells (and to a lesser extent the microvascular endothelium), thus driving acute cellular rejection reactions ( 16 , 23 , 24 ). Besides these key effector-target cell interactions, multiple secondary effectors, in addition to other cellular targets, are involved in VCA rejection ( 17 ).…”

“…Moris et al. further proposed an activating effect of T rm on NK cells in VCA rejection ( 24 ). In NK cells, this interaction coordinates increased granzyme B secretion ( 106 ).…”

“…IFN-g induces T h 1 responses and increases ROS levels, leading to endothelial damage in VCA grafts (104). Moris et al further proposed an activating effect of T rm on NK cells in VCA rejection (24). In NK cells, this interaction coordinates increased granzyme B secretion (106).…”

Sensitization and Desensitization in Vascularized Composite Allotransplantation

“…Vascular composite allotransplantation is an evolving field in organ transplantation since it has emerged as a viable option to repair tissue defects resulting from traumatic or other injuries in selected patients (1). Vascularized composite allografts (VCAs) consist of anatomically distinct tissues such as skin, muscles, connective tissue, bones and neurovascular elements that are transplanted as a single unit (2)(3)(4). So far, VCAs have been used in various settings including transplantation of face, upper or lower extremity, abdominal wall and genitourinary organs (4, 5) (1).…”

“…So far, VCAs have been used in various settings including transplantation of face, upper or lower extremity, abdominal wall and genitourinary organs (4, 5) (1). As with other solid organ grafts, they are limited by immune mediated rejection and a concomitant requirement for immunosuppression (2)(3)(4). Also, candidates for VCA are frequently sensitized, making them susceptible for antibodymediated rejection (AMR).…”