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The importance of histocompatibility matching for bone marrow transplantation between unrelated subjects was investigated retrospectively in a rhesus monkey preclinical model. Twenty-nine monkeys, conditioned with 900 rads of total body X-radiation and antilymphocyte serum (ALS) on day 0, received bone marrow transplants from unrelated donors on day 1. Proof of engraftment was indirect by early return of peripheral blood counts. All monkeys' lymphocytes were typed prior to transplantation for three to eight antigens at the postulated major rhesus histocompatibility locus, RhL-A.Matched recipients had no detected RhL-A antigens foreign to the donor, and this compatibility would theoretically lessen graft-versus-host discase (GVHD); all died with a median survival time (MST) of 35 days. In the case of mismatched marrow recipients, at least one of their detected RhL-A antigens was foreign to the donor, and these recipients had a MST of 14 days. The two groups were different at the 5 confidence level (Wilcoxon's rank sum test). Many mismatched monkeys survived only a few days longer than animals receiving no ALS and dying with acute GVHD. Limited RhL-A matching combined with pretransplant administration of ALS improved survival in marrow-grafted unrelated rhesus monkeys, probably because of retardation of GVHD. This is the first evidence that typing for lymphocyte alloantigens can significantly improve donor selection for bone marrow transplantation between unrelated primates.

Three rhesus monkey lymphocyte alloantigen groups have been defined by a cytotoxicity technique. Typing of 115 unrelated monkeys and 21 pedigreed families indicates that these antigens appear to be a part of one closely linked genetic system. These alloantigen groups may be the rhesus counterpart of the human HL-A alloantigens.

There has been much controversy as to the distribution of function of the sympathetic and parasympathetic nervous systems in the forebrain, particularly in the hypothalamus. Beattie and Sheehan1 found these systems to be separately represented, parasympathetic effects being obtained in the anterior region of the hypothalamus (tuber cinereum) and sympathetic effects in the posterior region. Ranson and his associates,2 however, have obtained sympathetic effects throughout the hypothalamus, including the tuber cinereum, as far forward as the optic chiasm. The only parasympathetic reaction regularly observed by them on hypothalamic stimulation was contraction of the urinary bladder, and this was found on stimulation in front of the optic chiasm. Among sympathetic effects they observed dilatation of the pupils, rise in blood pressure, secretion of epinephrine, secretion of sweat, inhibition of gastrointestinal peristalsis and erection of hair. Masserman and Haertig3 obtained parasympathetic effects on the gastrointestinal tract from both the

In a previous paper Darrow and Gellhorn1 showed that epinephrine in physiologic concentrations produces inhibitory effects on both branches of the autonomic nervous system. It was shown that in the presence of epinephrine the sympathetic responses of the pupil, blood pressure, nictitating membrane and foot pads (galvanic reactions) are reduced, and that the responses involving inhibition of the parasympathetic constrictor tonus of the sympathectomized eye are increased. The close association of sympathetic discharges with convulsions produced by insulin (Gellhorn2) and metrazol (Gellhorn and Darrow3) made it desirable to investigate whether the inhibitory effects of epinephrine extend to the somatic nervous system and lead to diminution or suppression of the convulsions. Such an investigation is particularly indicated because of the report by Hall and Leibel4 that epinephrine increases metrazol convulsions and the finding of Schweitzer and Wright5 that it inhibits the knee jerk. METHODS Insulin and

1. Increase in blood pressure induced by adrenalin or infusion of Ringer's solution leads to a decrease in pupillary diameter and to a relaxation of the nictitating membrane. A fall in the blood pressure induced by amylnitrite leads to a dilation of the normal and of the sympathectomized pupil. These observations indicate that a rise in blood pressure produces parasympathetic excitation and sympathetic inhibition, whereas a fall in blood pressure has the opposite results. 2. The effects produced by variations of blood pressure are still present after bilateral vagotomy and denervation of the carotid sinuses. 3. The effects of variations of blood pressure are not restricted to the visceral nervous system but extend to the somatic nervous system, inasmuch as increase in blood pressure is associated with decreased somatic excitability and decrease in pressure is associated with increased somatic excitability.

SUMMARY

Lethally irradiated rhesus monkeys were used in studies of allogeneic bone marrow transplantation. Animals given doses in excess of 812 rads survived an average of 11.7 days. Long-term survival was obtained in monkeys similarly irradiated and given autologous bone marrow cells. Irradiated monkeys given allogeneic marrow developed acute lethal graft-versus-host (GVH) disease with a mean survival time of 9.1 days. Eleven monkeys received allogeneic bone marrow following treatment with antilymphocyte serum (ALS) and lethal irradiation. Monkeys receiving ALS prepared in horses had less severe and less rapidly progressing GVH disease than untreated recipients. ALS prepared in rabbits was even more effective in preventing the acute GVH reaction and allowed survival times of up to 43 days. ALS-treated monkeys developed a subacute or chronic wasting syndrome which was clinically distinct from the severe acute GVH disease seen in unmodified allograft recipients. In addition, ALS-treated animals had prolonged depression of peripheral lymphocyte counts following transplantation in contrast to unmodified recipients which developed an early rise in circulating lymphocytes. It appears that ALS may act either upon donor immunocompetent cells and their precursors at the time of transplant or it may react with host-type cells which are the targets of donor immunocompetent cells. By the use of ALS, a primate model of subacute and chronic GVH disease can be produced which is suitable for studies of the mechanism and pathophysiology of the primate GVH reaction. The effectiveness of ALS in modifying acute primate GVH disease also suggests that further clinical trials of ALS in marrow transplant recipients are indicated.