Due to concerns of cross-reactivity between renal and islet allografts in initiation of rejection, we determined the ability of donor-specific and third-party splenic dendritic cells (DCs) and thyroids (whole-organ transplant) to initiate rejection of established islet allografts. Purified islets from neonatal F-344 (RT1Lv1) rats were transplanted bilaterally under the kidney capsule of Wistar-Furth (W/F, RT1u) rats without immunosuppression. The islet allografts were not rejected by 21 days posttransplantation. On day 22, freshly isolated or cultured DCs were injected intraperitoneally into the host. Both freshly isolated and cultured donor-specific (F-344) and some third-party (Buffalo, RT1b; ACI, RT1a) DCs initiated rejection of the islets as indicated by lymphocyte infiltration and destruction of the allograft. DCs, whether freshly isolated or cultured for 8 days from the recipient strain (W/F) and one third-party rat (Brown Norway, RT1n), did not initiate rejection. Splenic DCs from the Lewis (RT1l) rat, which has the same class I and II antigen haplotype as F-344 islet donor rats, also initiated rejection. Only 10(3)-10(4) DCs isolated from the spleen of donor rats were required to initiate rejection of the allograft. In a parallel series of W/F rats with islet allografts, a thyroid (half lobe) from the islet donor strain (F-344), recipient strain (W/F), or third-party rat (Buffalo, Brown Norway, or ACI) was inserted under the kidney capsule at 22 days post-islet transplantation. At 35 days, all thyroids and most islet allografts exhibited active or complete rejection after thyroid transplant from Buffalo, F-344, or ACI rats.(ABSTRACT TRUNCATED AT 250 WORDS)