Phase-Directed Therapy and Cardiac Xenograft Survival

Use of porcine tumor necrosis factor receptor 1‐Ig fusion protein to prolong xenograft survival

“…In a renal allograft primate model, systemic treatment with etanercept delayed the onset of rejection from 4.4 days in the untreated cohort to 11.7 days, but addition of a subtherapeutic dose of cyclosporin A (CsA, 11 days alone) delayed it much further (>38.5 days) [35]. Combination of systemic anti-TNF antibody with CsA or CsA plus cyclophophamide also markedly improved xenograft survival in a hamster-to-rat cardiac xenotransplant model [13]. A synergistic effect was also observed when combining anti-TNF antibody therapy with L-NAME, an inhibitor of nitric oxide production, in a concordant heart xenotransplant model [12].…”

“…TNF potent proinflammatory activity plays a major role in the progress of a variety of human diseases and contributes to allograft rejection [33][34][35]. Several studies also point out TNF involvement in xenograft rejection [12][13][14][15][16][17][18][19]. In this work, we have developed a strategy that inhibits very strongly TNF on the graft site and thus prolongs xenograft survival.…”

“…Our approach presents several advantages compared with other systems previously developed. First, there are a limited number of studies focused on inhibiting TNF in a xenogeneic setting [12][13][14][15]. The majority use systemic treatments with anti-TNF antibodies with the aim to test the contribution of TNF to xenograft rejection [12][13][14][15]36,37].…”

“…In addition, extensive work has shown the ability of TNFa to reject transformed cells xenografted into mice [18,19]. Although the contribution of TNF to delayed rejection of cells, tissues and organs may need further investigation, especially in primates, many studies to date support the involvement of TNF in xenograft rejection [12][13][14][15][16][17][18][19].…”

Identification of soluble and membrane‐bound isoforms of porcine tumor necrosis factor receptor 2

“…The contribution of TNF to solid organ xenograft rejection was initially demonstrated in small‐animal transplant models using inhibitory antibodies to TNF [26,27]. The role of this cytokine in the rejection of xenogeneic pancreatic islets was also confirmed in mice [28].…”