Physiological obstacles after xenotransplantation

Abstract

The incompatibility of allografts is restricted to immunologic factors such as the MHC class I and class II antigens. Anatomic, physiological, and biochemical characteristics are identical. This is completely different in xenografts. The upright position of man is unique in nature. Gravity therefore exerts a different impact on the anatomic situation of organs such as lung, heart, liver, and kidney. More pronounced are differences on the humoral and enzymatic basis. Complex interactions existing in allografts are totally disturbed in xenogeneic situations. Up- and downregulation controlled by releasing factors on the one hand and inhibitors on the other must be species-specific. These actions of mainly proteases are both fast and in most cases depend on species-specific receptors. Examples are growth hormones which could stimulate the xenografts to unrestricted growth, as in pig hearts in the human patient. Enzymes not metabolized by the liver would constantly stimulate mechanisms to a level that is not compatible with life, and other reactions could be more expressed in the donor species than in man and thus disturb these interactions. Products like albumin are carriers for other molecules and need to be compatible for binding sites. Pig and human albumin have an amino acid identity of less than 65% erythropoetin (EPO) of less than 82%, and complement of less than 70%. All factors are obviously without specific function in the future recipient, the human patient. In contrast, pig complement would, as a foreign molecule, induce the alternative complement pathway in the human recipient, leading to unknown side effects. It is not sufficiently investigated whether under such physiological and anatomic differences a long-term survival of xenograft or recipient is possible--a chain is as strong as its weakest link.