SEQUENTIAL CELLULAR AND MOLECULAR KINETICS IN ACUTELY REJECTING RENAL-ALLOGRAFTS IN RATS

The initial (0-24 hr), early (3-5 days), and late (7-14 days) events o ccurring in LBNF1 renal allografts transplanted into Lew recipients we re examined to define precisely the sequential cellular and molecular kinetics during acute rejection. Grafts and spleens were harvested at 3, 6, 12, and 24 hr, and at 3, 5, 7, and 14 days and processed for mor phology, immunohistology, and reverse transcriptase-polymerase chain r eaction. Various factors (mRNA) were up-regulated sequentially in the allografts over time. In the initial phase, E-selectin and complement (C1 and C3) expression was noted within 6 hr, peaking by 24 hr. RANTES (regulated upon activation, normal T cell expressed and secreted) inc reased within 6 in, and then again between 3 and 6 days. By immunohist ology, MHC class II was up-regulated consistently after day 1. Interce llular adhesion molecule-1 expression increased after day 3; lymphocyt e function-associated antigen-1(+) infiltrating leukocytes peaked at d ay 5. Infiltrating CD8(+) T lymphocytes increased strikingly between d ays 1 and 3, peaking at day 5; CD4(+) cells infiltrated more slowly un til day 5. The kinetics of ED1(+) macrophages were similar to those of lymphocyte function-associated antigen-1(+) cells. The CD4(+) T cell- derived product, interleukin (IL)-2, peaked at 7 days. Interferon-gamm a increased progressively up to 14 days. By 3 days, the macrophage-ass ociated factor, transforming growth factor-beta, peaked; this was foll owed by increased IL-6 expression by day 5. IL-1, tumor necrosis facto r-alpha, and inducible nitric oxide synthase increased slowly until da y 7, declining thereafter. Endothelin increased progressively over the 14-day follow-up period. Cytokine dynamics occurring in host spleen w ere similar to those noted in the allografts. Although acute rejection is primarily T cell mediated, adhesion molecules, macrophages, and th eir associated products may influence initial and later changes. The b risk expression of complement, E-selectin, and RANTES within the first few hours after engraftment may occur secondary to ischemic injury an d trigger subsequent immunological events. Macrophages and their produ cts may play a larger role in the process than hitherto appreciated.