Graft rejection in a congenic panel of rats with defined immune response genes for class I antigens. II. Quantitative aspects of Ir gene function in a full-haplotype mismatch.

Previous studies have shown that the Ir-gene-controlled rejection of rl tissues by c/u responder and non-rejection by c low responders does not extend to tissues expressing a full a haplotype mismatch. However, antibody responses and liver graft rejection are both defective in low responders, even across a full haplotype barrier. We have therefore used a titrated adoptive transfer assay to search for quantitative differences in the responsiveness of c and c/u animals to a organ grafts. We first established that a heart graft rejection could be ablated in both recipient strains with whole-body irradiation and could be restored with syngeneic cells. Titration of restorative cells revealed that 5 times as many c cells were required to restore graft rejection in c recipients as c/u cells were required in c/u recipients. Use of cells from primed donors showed that in both c/u and c animals these cells had undergone about a 5-fold increase in potency, showing that there was no failure of proliferation and differentiation in the low responder after contact with antigens. Cross-transfer experiments were done to attempt to localize the defect in low-responder animals either to a failure of low-responder antigen-presenting cells (APC) to trigger a response or a defect in the responsiveness of alloreactive cells toward the a antigens. In these experiments c cells were obtained from radiation chimeras of the c----c/u type. These cells were used to restore graft rejection in c/u irradiated recipients. Similar experiments employing c/u cells obtained from c/u----c chimeras and given to irradiated c recipients were also done. These showed that c cells from chimeras were marginally less potent than c/u cells from chimeras. In contrast when cross-transfer of c/u cells to c animals bearing a nonrejected rl heart was done, no rejection was seen even when antigen presenting cells were cotransferred. The conclusions from this series of experiments were that quantitatively small defects were present in both repertoire and antigen presentation, and that these quantitative defects in aggregate were probably sufficient to explain the documented low responsiveness of c animals to the a haplotype. The failure of high-responder c/u cells to secure rejection of rl tissues in the low-responder c environment suggests that presentation of isolated class I differences in host APCs is mandatory for rejection to occur and is highly defective in the c animal.

A novel cell type carrying both Th and Tc/s markers in the blood of cyclosporine-treated, allografted rats.

During treatment of heart-grafted rats with cyclosporine, an unusual large lymphocyte appears in the blood. These cells constitute up to 40% of the peripheral blood leukocyte population and carry both the T helper/DTH and T cytotoxic/suppressor differentiation antigens. They require both the allograft and CsA for their generation and are not recently thymus-derived. They gradually disappear after stopping CsA treatment, although the treated rats remain tolerant of the graft.

Observations on pituitary and cerebral catecholamines in Brattleboro rats.

The combined neural and intermediate lobes (N.I.L.) of the pituitary glands of Brattleboro rats contained significantly more noradrenaline (NA) than those of normal controls of the same age. In addition, in 4 and 6 months old rats the N.I.L. of the homozygotes (Di-rats) contained about twice as much NA as those of the heterozygotes (non-Di-rats). In the enlarged and hyperaemic neural lobes of the Di-rats enlarged blood vessels could be seen. They were surrounded by a rich network of nerve fibres which displayed catecholamine fluorescence. The NA concentrations in the medial basal hypothalamus (M.B.H.) of 4, 6, and 9 months old Di-rats were significantly higher than those of the non-Di-rats and of controls of the same age. This may contribute to the diminished ACTH secretion in Brattleboro rats. The total amount of DA contained in the N.I.L. of 9 months old Di-rats was 20% lower than in the non-Di-rats of the same age. The concentrations of homovanillic acid (HVA) in the corpora striata of 4 months old Di- and non-Di-rats was significantly higher than in older Brattleboro rats and in control rats of various strains and ages. At 9 months it was nearly twice as high in the Di-rats as in the non-Di-rats. The concentrations of dihydroxyphenylacetic acid in the striata of 4--6 months old Di- and non-Di-rats were higher than those of Long Evans rats of the same age.