title: The fourth barrier.
abstract: At the entrance of a new era, clinical xenotransplantation is a valued and auspicious option in tackling the problem of donor shortage. Because of ethical and anatomical issues, domestic farm animals are considered the most favourable species for organ donation, but transplantation of their organs leads to a complex process of rejection. Mechanistically, three immunological barriers, namely hyperacute rejection, delayed xenograft rejection and a subsequent cellular rejection, are distinguished. A fifth (microbiological) barrier is also being recognised. This review focuses on problems regarding the fourth barrier, i.e. physiology, in possible clinical settings and their corresponding animal models. Besides anatomical differences and posture, biochemical differences may have a severe impact on recipient survival. Differences in blood components and electrolyte and other biochemical concentrations are easily detected throughout the species considered for xenotransplantation. Enzymes and hormones have complex routes of action, activation and inhibition, and their molecular differences can impede function. As infusion or medicine may correct certain imbalances in electrolytes and proteins, problems with complex interactions might be difficult to retrieve and solve. Experimentally, survival of discordant xenografts show promising results, but the first physiological problems have already been detected. So, based upon the few experimental data available and the comparison of veterinary physiology, one might expect differences between the organs grafted, regarding the possible occurrence of physiological problems. Moreover, precautions must be taken to extrapolate long-term survival, because of species specificity.
authors.affiliation: Department of Surgery, Erasmus University Rotterdam, The Netherlands.
authors.forename: E O
authors.initials: EO
authors.lastname: Schraa
authors.forename: R L
authors.initials: RL
authors.lastname: Marquet
authors.forename: J N
authors.initials: JN
authors.lastname: IJzermans
mesh_terms: D000208:Acute Disease; D000818:Animals; D006084:Graft Rejection / Q000276:immunology; D006085:Graft Survival / Q000276:immunology; D006801:Humans; D007111:Immunity, Cellular; D014181:Transplantation Immunology / Q000276:immunology*; D014183:Transplantation, Heterologous / Q000276:immunology*