AUTOIMMUNITY, HYPOREACTIVITY TO T-CELL MITOGENS AND LYMPHOPROLIFERATIVE DISORDERS FOLLOWING NEONATAL INDUCTION OF TRANSPLANTATION TOLERANCEIN MICE

We have reported that, in A/J (A) (H-2(a)) mice, a partial tolerance t o C57BL/1OScSn (B10) (H-2(b)) skin allografts and a high incidence of lethal lymphoproliferative disorders (LPD) can be induced by the neona tal i.v. injection of 2 x 10(7) semiallogeneic (B10 x A)F-1 spleen cel ls (SC) (Vegh, P., Baranyi, L. and Janossy, T, Cell. Immunol. 1990. 12 9: 56). In this study, we show that the incidence and mortality of LPD were continuously growing from 1 month of age until the end of the ex periment at 1 year (64% and 36%, respectively). Based on histology, 27 % of the diseased mice suffered from lymphoid malignancies. In the rem aining cases (73%), reactive histopathological changes were seen in th e spleen, lymph nodes (LN), liver and kidneys. The proportion of CD4() T cells in the spleen and LN as well as that of splenic B cells decr eased, while the percentages of mature and immature myeloid cells doub led. The total cell number of each (sub)population, however, was eleva ted in both lymphoid organs. The cells taking part in the lymphoprolif eration were of host (A) and not of donor (F-1) origin. Preceding the development of apparent LPD, the SC, LN cell and thymus cell suspensio ns of 1-month-old tolerized mice showed reduced in vitro proliferative responses to T cell and T cell-dependent B cell mitogens (Con A or PW M), while their reactivity to a T cell-independent B cell mitogen (lip opolysaccharide) was essentially unimpaired. This hyporeactivity seems to be functional, because neither histology nor immunophenotyping by flow cytometry revealed significant alterations in the spleen and thym us of such animals, apart from a slight reduction in the ratio of CD4( +)/CD8+ T cell subpopulations in the spleen. The in vivo T cell-mediat ed immune response of the tolerized mice was practically normal to thi rd party CBA/Ca (H-2(k)) allografts. Antithymocyte autoantibodies (ATA ) were detected in the sera of 76% of the tolerized mice at I month of age (i.e., even before the mass appearence of LPD). ATA as well as an tinuclear Ab were present in 65% of the adult tolerized mice, independ ently of the presence of LPD. Taken together, in A mice neonatally inj ected with (B10 X A)F-1 SC, a partial, specific allograft tolerance an d a chronic host-vs.-graft disease-like syndrome developed. The latter is manifested in hyporeactivity to T cell mitogens, development of au toantibodies and, subsequently, in progressive LPD and lymphoid malign ancies.