Engraftment of severe combined immune deficient mice receiving allogeneic bone marrow via In utero or postnatal transfer.

Although in utero transplantation (IUT) has been shown to be effective in treating human severe combined immune deficiency (SCID), the relative merit of IUT as compared with postnatal bone marrow transplantation (BMT) for SCID is unknown. Therefore, comparative studies were undertaken in mice to determine the engraftment outcome in these two settings. Because T-cell depletion (TCD) reduces graft-versus-host disease (GVHD) severity but compromises alloengraftment, studies were performed with TCD or non-TCD BM and GVHD risk was assessed using a tissue scoring system and by the adoptive transfer of splenocytes from engrafted mice into secondary recipients. Non-SCID recipients received pre-BMT irradiation to simulate those circumstances in which conditioning is required for alloengraftment. IUT recipients of non-TCD and especially TCD BM cells in general had higher levels of donor T-cell and myeloid peripheral blood (PB) engraftment than nonconditioned SCID recipients. Increased TCD or non-TCD BM cell numbers in adult SCID recipients resulted in similar levels of PB engraftment as IUT recipients. However, under these conditions, mean GVHD scores were higher than in IUT recipients. The majority of adoptive transfer recipients of splenocytes from IUT recipients were GVHD-free, consistent with the in vitro evidence of tolerance to host alloantigens. Total body irradiation (TBI)-treated mice that had the highest engraftment had evidence of thymic damage as denoted by a higher proportion of thymic and splenic T cells with a memory phenotype as compared with IUT recipients. IUT mice had vigorous thymic reconstitution by 3 weeks of age. Our data indicate that IUT has a number of advantages as compared with postnatal BMT. Future studies examining the fine specificity of immunoreconstitution in IUT versus postnatal BMT are indicated.

Effects of aging on cerebral vascular responses to serotonin in rats.

The purpose of this study was to examine effects of aging on responses of large cerebral arteries to serotonin. We measured cerebral microvascular pressure (with a micropipette and servo-null method), diameter of pial arterioles, and cerebral blood flow (microspheres) in adult (12- to 14-mo-old, n = 15) and aged (24- to 27-mo-old, n = 14) Wistar rats. Responses to intra-atrial infusion of serotonin (5 and 50 micrograms.kg-1.min-1) were examined. Infusion of the low dose of serotonin decreased mean arterial pressure and pial arteriolar pressure in adult and aged rats to similar levels. Cerebral blood flow was not reduced in adult or aged rats during infusion of the low dose of serotonin. The high dose of serotonin did not affect mean arterial pressure but reduced pial arteriolar pressure [from 46 +/- 4 to 23 +/- 2 (SE) in adult rats and from 52 +/- 3 to 18 +/- 4 mmHg in aged rats]. The high dose of serotonin increased large-artery resistance from 0.9 +/- 0.1 to 1.6 +/- 0.2 in adult rats and from 0.9 +/- 0.1 to 2.7 +/- 0.6 mmHg.ml-1.min.100 g in aged rats. Cerebral blood flow was reduced significantly in aged rats (from 59 +/- 3 to 41 +/- 6 ml.min-1.100 g-1), but not in adult rats, during infusion of the high dose of serotonin. We conclude that aging augments constrictor responses of large cerebral arteries to intravascular serotonin, which results in a reduction of cerebral blood flow in aged but not adult rats.