NEONATAL TRANSPLANTATION TOLERANCE IS ASSOCIATED WITH A SYSTEMIC REDUCTION IN MEMORY CELLS, ALTERED CHIMERIC CELL PHENOTYPE, AND MODIFIED EICOSANOID AND CYTOKINE PRODUCTION

Certain B10 background mice are resistant to tolerance induction follo wing a neonatal inoculation of semiallogeneic class I/II MHC-disparate cells despite early thymic clonal deletion of alloreactive cells, The emergence of memory T cells and persistence of particular chimeric ce lls in the thymus has an association with this resistance. In these st udies, we utilized a hemisplenectomy technique to examine systemic cel l populations of adult B10.S (H2(s), H2E(-)) mice that received (B10.S xB10.A)F-1 cells at birth and before and following application (and re jection or acceptance) of B10.A (H2(k/d), H2E(+)) skin grafts, Prior t o skin graft challenge, tolerant mice had reduced splenic levels of me mory (CD45(hi), PgP-1(hi), Mel-14(neg))T cells as compared with the re jecting recipients and following B10.A graft challenge, the nontoleran t mice showed a further increase in these cells, Elevated pretransplan t levels of donor H2K(k)+ cells coexpressing B220, CD11b, or CD3 were seen in the tolerant mice. Following skin grafting, splenic chimerism was reduced with differing chimeric cell phenotypes between the tolera nt and nontolerant mice. In vitro production of PGE(2) in a MLC was de layed in the tolerant mice with minimal production of IL-2 and IL-4, N ontolerant mice made high levels of TxB(2) and heightened, early produ ction of IL-2 and IL-4 during the MLC, Thus, tolerance induction is as sociated with increased numbers of particular chimeric cells, fewer pe ripheral lymphoid immunocompetant memory T cells, impaired eicosanoid secretion, and reduced alloreactivity and alloantigen-driven IL-2/IL-4 production, It appears that alloreactive cells necessary to break tol erance are generated when fewer class II+ (e.g., B220(+), CD11b(+)) ch imeric cells are present and that there is a coexistence of effector a nd regulatory T cell subpopulations in the nontolerant mice, By compar ison, tolerance acquisition does not appear associated with the presen ce or generation of a predominant subtype of T cell but rather is like ly more dependent upon clonal deletion processes.