Arterial pressure response to endothelin-1 and sarafotoxin 6c in rescued endothelin-B-deficient rats.

The spotting lethal rat carries a naturally occurring deletion of the endothelin-B- (ET(B)) receptor gene that prevents expression of functional ET(B)-receptors. Gariepy and colleagues used tissue-specific ET(B) transgene expression to support normal enteric nervous system development. To determine functional consequences of ET(B)-receptor deficiency, studies were conducted to characterize the pressor response to endothelin-1 (ET-1) and the ET(B) agonist, sarafotoxin 6c (S6c) in transgenic rats homozygous for the ET(B)-deficiency (sl/sl). Similar transgenic rats heterozygous for the ET(B) deficiency were used as controls (sl/+). All rats were anesthetized with Inactin (100 mg/kg, i.p.) and a tracheostomy performed. The right carotid artery and right jugular veins were catheterized for measuring mean arterial pressure (MAP) and infusion of peptides, respectively. Following baseline measurement of MAP, hexamethonium was infused (10 mg/kg) to block sympathetic reflex responses. After a 10-15 min stabilization period, ET-1 or S6c was infused at 0, 1, 0.3 and 1.0 nmol/kg at 10 min intervals. MAP in the two groups of anesthetized rats was similar during the baseline period. The sl/+ rats showed a classic dose-dependent pressor response to ET-1; a transient vasodilation followed by prolonged vasoconstriction. In contrast, the vasodilation was absent in sl/sl rats. Furthermore, ET-1 was more potent in sl/sl compared to the sl/+ rats. The response to S6c was qualitatively similar to ET-1 in the sl/+ rats. However, the sl/sl rats also had a significant pressor response to the ET(B) agonist, S6c. These studies provide in vivo evidence that the rescued ET(B)-deficient rat lacks functional vasodilatory ET(B) responses in response to ET-1 but retains the vasoconstrictor response to ET(B)-receptor agonists.

HLA-G functions as a restriction element and a transplantation antigen in mice.

HLA-G, a human MHC class I molecule expressed on the trophoblast during pregnancy, was expressed in transgenic mice by recombining the HLA-G gene with a transcriptional promoter from a murine H-2 MHC class I gene. Skin grafts from HLA-G transgenic mice were rejected by non-transgenic mice showing that HLA-G behaves as a xenotransplantation antigen in mice. Further investigation revealed that murine T cells recognize native HLA-G directly as a xenoantigen or they recognize processed peptides derived from HLA-G presented in the context of murine MHC molecules. HLA-G molecules also function as restriction elements capable of presenting peptides to murine T cells since immunization of HLA-G transgenic mice with peptide that binds specifically to HLA-G molecules elicited HLA-G-restricted, cytotoxic T cell responses. In addition, murine T cell responses to human xenoantigens are enhanced when responder cells originated from HLA-G transgenic mice. Based on these observations, we conclude that expression of HLA-G molecules influences selection of the murine T cell repertoire and that HLA-G exhibits immunological properties that are indistinguishable from classical HLA class I molecules when expressed in transgenic mice. Thus, any unique immunological functions mediated by HLA-G must arise from the distinctive, trophoblast-specific pattern of HLA-G expression in humans and not from structural peculiarities of HLA-G molecules.