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

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.