Manipulation of brain DNA synthesis is achieved by using a systemic immunological disease

Abstract

Previously, we showed that as early as postnatal day 11 an immunological disease, graft-versus-host disease, induced by grafting allogeneic lymph node cells into an immunoincompetent neonatal rat significantly decreases cerebellar histogenesis--i.e., DNA synthesis and the number of newly formed neurons. Here, we report that, subsequent to successful immunotherapy, there was a reversal of the deleterious graft-versus-host disease-induced alterations in DNA synthesis in individual cerebellar germinal cells. Immunotherapy involved treating the diseased rats on postnatal days 11, 12, and 13 with alloantiserum specifically directed against the grafted lymph node cells injected on the day of birth. On postnatal day 14, diseased, serum-treated, and control littermates were injected with [3H]thymidine and, 15 min later, the cerebella were excised and autoradiographed. A 0.72-mm segment of the external granular layer in the cerebellar fissure between lobules VIB and C was searched for labeled cells. The control group had the greatest number of labeled cells, defined by the presence of six or more autoradiographic grains. (43 +/- 4, mean +/- SEM) and the greatest number of grains per cell (9.5 +/- 0.2). Rats with the disease had few labeled cells (4 +/- 2) and the number of grains per cell was low (6.6 +/- 0.6); however, serum treatment increased both the number of labeled cells (26 +/- 8) and the number of grains per cell (7.4 +/- 0.2). These results show that without mononuclear infiltrates or inflammation in the cerebellum, a systemic immunological disease can dramatically decrease DNA synthesis per germinal cell and, moreover, that halting the disease by alloantiserum therapy can reverse this effect. These findings emphasize the sensitive plastic nature of neuronal cell acquisition in the normally developing brain.