T cells from an HLA-DR11/DR12 responder were stimulated in mixed lymphocyte culture with cells carrying the DR1 antigen. After priming, T cells proliferated in response to both DR1-positive-stimulating cells and a peptide derived from a polymorphic region of the HLA-DR beta 1*0101 chain presented by responder's antigen-presenting cells (APC). The dominant epitope recognized by the primed T cells corresponded to residue 21-42 and was presented by the responder's HLA-DR12 antigen. The DR1 peptide-reactive T cells express T cell receptor V beta 3. The results demonstrate that allopeptides derived from the processing and presentation of donor major histocompatibility complex molecules by host-derived APC trigger alloreactivity. The frequency of T cells engaged in the indirect pathway of allorecognition is about 100-fold lower than that of T cells participating in the direct recognition of native HLA-DR antigen. However, indirect allorecognition may play an important role in chronic allograft rejection, a phenomenon that is mediated by the activation of T helper cells and of alloantibody-producing B cells.

The major threat to long-term survival of heart allograft recipients is the development of graft atherosclerosis, which seems to be a manifestation of chronic rejection. To assess the role of anti-HLA antibodies in heart allograft rejection we studied 107 patients and compared the survival of recipients who formed anti-HLA antibodies with the survival of recipients who developed no antibodies. At 4 years the actuarial survival was 90% in the nonproducer group and 38% in antibody-producers (P=0.038). We further explored the possibility that HLA antigens from the injured graft are released into the circulation and can be found in the serum either free or complexed with anti-HLA antibodies. This hypothesis was confirmed by the finding that the frequency of sera containing soluble HLA antigens from the graft or immune complexes of HLA alloantigens with anti-HLA antibodies was significantly higher in patients who rejected compared with patients with successful heart allografts (P <0.05). Following depletion of soluble HLA antigens, anti-HLA antibodies became detectable in 53% and 74% sera obtained during the first and second year posttransplantation, respectively, from patients undergoing chronic rejection. Long-term survivors showed a significantly lower (P <0.001) frequency of anti-HLA antibodies in sera depleted of HLA antigens. Lastly, studies of anti-anti-HLA-A2 and A3 antibodies in recipient sera suggest that quiescence is maintained by antiidiotypic antibodies.

We studied the biological effects of pluripoietin, a human pluripotent hemopoietic colony-stimulating factor (CSF) purified from the 5637 bladder carcinoma cell line. We found that this human CSF appears to be a unique hemopoietic growth factor, differing from interleukin 3 (IL-3) by virtue of its leukemia differentiating activity in mouse and man, and from mouse granulocyte CSF, which does have differentiation-inducing activity, but lacks pluripoietic activity. In addition, differences from IL-3 were observed in cross-species activity on normal and leukemic cells.

Diabetes results from an absolute or relative reduction in pancreatic β cell mass (BCM) leading to insufficient insulin secretion and hyperglycemia. Measurement of insulin secretory capacity is currently used as a surrogate measure of BCM. However, serum insulin concentrations provide an imprecise index of BCM, and no reliable noninvasive measure of BCM is currently available. Type 2 vesicular monoamine transporters (VMAT2) are expressed in human islet β cells, as well as in tissues of the CNS. [¹¹C]Dihydrotetrabenazine ([¹¹C]DTBZ) binds specifically to VMAT2 and is a radioligand currently used in clinical imaging of the brain. Here we report the use of [¹¹C]DTBZ to estimate BCM in a rodent model of spontaneous type 1 diabetes (the BB-DP rat). In longitudinal PET studies of the BB-DP rat, we found a significant decline in pancreatic uptake of [¹¹C]DTBZ that anticipated the loss of glycemic control. Based on comparison of standardized uptake values (SUVs) of [¹¹C]DTBZ and blood glucose concentrations, loss of more than 65% of the original SUV correlated significantly with the development of persistent hyperglycemia. These studies suggest that PET-based quantitation of VMAT2 receptors provides a noninvasive measurement of BCM that could be used to study the pathogenesis of diabetes and to monitor therapeutic interventions.