title: Blockade of central and peripheral luteinizing hormone-releasing hormone (LHRH) receptors in neonatal rats with a potent LHRH-antagonist inhibits the morphofunctional development of the thymus and maturation of the cell-mediated and humoral immune responses.
abstract: The development of the thymus and the hypothalamic-pituitary-gonadal axis are linked by bidirectional hormonally mediated relationships. In the present study, the direct involvement of the neuropeptide LHRH in the maturation of the thymus and development of the cell-mediated and humoral immune responses were assessed after treatment of neonatal (from post-natal day 1-day 5) female rats with a potent LHRH-antagonist (LHRH-anta, p-Glu-D-Phe 2.6,Pro3-LHRH, 50 micrograms/rat), and the effects compared to those resulting from neonatal castration. Whereas in control animals the maturation of mitogenic potential in thymocyte cultures showed a progressive and age-dependent increase, reaching a maximal activity at 30 days of age and then decreasing after puberty onset, in LHRH-anta-treated rats, the thymocyte's proliferative response was completely blocked at 7 days of age and remained very low at each time interval studied, until 3 months of age. A similar effect of the LHRH-anta treatment on splenocyte cultures was measured. Moreover, a reduced percentage of the T-helper lymphocyte subpopulation followed LHRH-anta administration. By contrast, in neonatally castrated rats, blastogenic activity was significantly higher, compared to control cultures, at each stage studied. Treatment with LHRH-anta produced a significant decrease in thymus wt, an alteration of the maturational pattern characterized by a cellular monomorphism, reduced thymocyte volume, reduction of the cortical area, and depauperation of the epithelial microenvironment. Moreover, a morphometric analysis revealed a selective decrease in the large lymphoid cell population of the subcapsular cortex at 7 and 15 days. On the other hand, neonatal castration produced an opposite effect, leading to a marked hypertrophy of the cortical area, and counteracted the post-puberal thymus atrophy. When LHRH-anta-treated adult (3-month-old) rats were challenged with an antigenic stimulus (multiple sc injections of complete Freund adjuvant and BSA) and antibody (anti-BSA antibodies of the immunoglobulin G class) production measured in the serum after 15 days, a marked and significant decrease in immunoglobulin G levels was observed, compared to the values measured in untreated control. The described immune deficiencies in LHRH-anta-treated rats were associated with a clear inhibition of sexual maturation. This study clearly indicates that the blockade of central and peripheral LHRH receptors during a critical period for maturation of both hypothalamus-hypophyseal-gonadal axis and brain-thymus-lymphoid axis dramatically impairs immune system development, suggesting a potential role of the neuropeptide LHRH in the bidirectional programming of both neuroendocrine and immune functions.
authors.affiliation: Department of Pharmacology, Medical School, University of Catania, Italy.
authors.forename: M C
authors.initials: MC
authors.lastname: Morale
authors.forename: N
authors.initials: N
authors.lastname: Batticane
authors.forename: G
authors.initials: G
authors.lastname: Bartoloni
authors.forename: V
authors.initials: V
authors.lastname: Guarcello
authors.forename: Z
authors.initials: Z
authors.lastname: Farinella
authors.forename: M G
authors.initials: MG
authors.lastname: Galasso
authors.forename: B
authors.initials: B
authors.lastname: Marchetti
mesh_terms: D000818:Animals; D000831:Animals, Newborn / Q000502:physiology*; D000917:Antibody Formation / Q000502:physiology; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism; D007111:Immunity, Cellular / Q000502:physiology*; D016131:Lymphocyte Subsets / Q000166:cytology; D009929:Organ Size; D010053:Ovary / Q000378:metabolism; D010902:Pituitary Gland / Q000378:metabolism; D051381:Rats; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors*; D012741:Sexual Maturation; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013950:Thymus Gland / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism
chemical_list: D011956:Receptors, Cell Surface; D007987:Gonadotropin-Releasing Hormone