The fetal lamb in utero is able to form large amounts of specific antibody in response to antigenic stimulus as early as the 66th to 70th day of the 150 day gestation period. Among the several antigens employed, the fetal lamb responded earliest, and with the highest titers, to bacteriophage φX. Slightly less effective as an antigen was horse ferritin, while ovalbumin proved to be a weak antigen, especially in younger fetuses. Ineffective in stimulating an antibody response at any time during fetal or early neonatal life were diphtheria toxoid, Salmonella typhosa, and BCG. Thus, it may not be feasible to fix precisely the time of onset of immunologic responsiveness in a species, inasmuch as it appears to differ so greatly from one antigen to another. The quantity of antibody found 10 days after φX immunization was not significantly different in fetuses injected at 60 to 120 days of gestation. The earliest anti-phage antibody produced by the lamb fetus is a macroglobulin sensitive to the action of 2-mercaptoethanol. Only in older fetuses with longer lasting stimuli were appreciable amounts of 7S γ-globulin antibodies formed. The conformity of these observations to theories on the ontogenesis of the immune response is discussed.

Recent evidence has indicated that the ability to develop an immunologic response to antigenic stimulus first appears during the fetal stage ir~ certain species (1--4). Earlier papers in this series (5, 6) have indicated that the fetal lamb in utero is able to form antibodies as early as the first half of gestatiola. Curiously, the time of maturation of the immune response in these ~etuses seems to be a function of the antigen employed. While bacteriophage cX 174 stimulates antibody formation before the 53rd day of gestation, horse ferritin does not assume antigenicity until about the 65th day, nor does ovalbumin until about the 125th day. Substances such as diphtheria toxoid mad Salrao~eUa typhosa were found to be ineffective throughout fetal life as elicitors of an antibody response.Schinkel and Ferguson (7) reported that the fetal lamb is able to reject allogeneic skin grafts specifically at about the ll7th dayof gestation. This study of rejection of orthotopic skin grafts in the fetal lamb was tmdert~ken (a) to confirm the observations of Schinkel and Ferguson; (b) to determine the earliest fetal age at which allogeneic graft rejection would occur; (c) to study the rate of graft rejection in the young fetus; (d) to examine the effect on graft rejection of various donor-recipient relationships; (e) to evaluate the morphologic and serologic changes accompanying the rejection process; and (/) to clarify the role of circulating antibody in the mechanism of graft rejection. The latter investigation, a preliminary report of which has appeared elsewhere (8), is made possible by the unique situation that exists in the ovine fetus, which receives no maternal y-globulin across the placenta and synthesizes little or none itself (6, 9).

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