No abstract

The CD26 antigen, one of the major costimulatory molecules in T cell activation, was shown to possess dipeptidyl peptidase IV (DPP IV) activity. Previously, we demonstrated that immunosuppressed kidney transplant patients exhibit lower DPP IV serum activity as compared with healthy individuals. In the present study, we analyzed the role of CD26/DPP IV in the immune cascade triggered by organ transplantation and leading to acute rejection of cardiac allografts in rat recipients. Transplantation of hearts from (Lewis x Brown Norway)F1 donors into Lewis hosts resulted in an early (24 hr) increase in cellular CD26 expression, followed by a rise in DPP IV serum activity, which peaked at day 6, i.e., before the time of actual graft loss. Specific targeting of DPP IV activity with a novel, low-molecular-weight inhibitor of the diphenyl-phosphonate group (prodipine) abrogated acute rejection and prolonged cardiac allograft survival to 14.0+/-0.9 days (P<0.0001). Prodipine treatment prevented the early peak of cellular CD26 expression and thoroughly suppressed systemic DPP IV activity. The inhibition of DPP IV was associated with severely impaired host cytotoxic T lymphocyte responses in vitro. These results demonstrate the role of CD26/DPP IV in alloantigen-mediated immune regulation in vivo and provide the first direct evidence that CD26/DPP IV plays an important role in the mechanism of allograft rejection. The model of targeting CD26/DPP IV may reveal essential interactions on the level of costimulatory alternate T cell activation pathways, allowing a more subtle approach for more selective immunosuppression in transplant recipients.

No abstract

Both AP-1 and STAT-1 dODN treatments suppress graft endothelial adhesion molecule expression, reduce graft infiltration and in turn significantly delay acute rejection. The utilization of dODNs in the cardioplegic solution might be a novel strategy to protect transplanted organs from early damage during transplantation, to preserve organ function and bridge the critical phase after transplantation when standard immunosuppression is not yet completely effective.

Quantitative measurement of specific mRNA species is of major importance for approaching many fundamental questions in biology. Until now, quantitation of gene expression has usually been done by Northern blotting, but this procedure is relatively insensitive, requiring microgram amounts of RNA. Furthermore, unless linear ranges of RNA concentration are determined, the procedure is semiquantitative at best. Because of the limitations of Northern blotting, various strategies have been developed for quantitation of cDNA by polymerase chain reaction (PCR)-based methods (1-3), most of them utilizing the principle of competitive PCR in which a synthetic segment is coamplified along the target DNA segment. We were interested in comparing the expression of drug target genes in very small samples of human tumor material, such as would be obtained from biopsies or even paraffin blocks. The competitive PCR was not entirely suitable for this purpose because: (1) the "input" RNA or DNA concentration must be known with precision in order to provide a normalization factor, and (2) our results suggested that the competitor and target were not necessarily amplified with the same efficiency even when the segments to be amplified were the same size (4). To overcome these problems, we developed an alternate method of PCR quantitation with the following key features:

Treating donor hearts with decoy ODNs neutralizing AP-1 or STAT-1 at the time of transplantation prevents upregulation of CD40 expression in the graft coronary arteries and effectively inhibits CAV.

No abstract

Summary It is unclear to what extent patients awaiting heart transplantation (HTx) engage in physical activities. We examined the everyday physical activity and its associations with depressive symptoms and disease severity in 318 patients newly registered for HTx in the multi‐site study ‘Waiting for a New Heart’ (aged 53.5 ± 11.4 years, 18% female patients). Participants completed questionnaires assessing depressive symptomatology and physical activity (number of physical activities, caloric expenditure associated with each activity), and estimated the distance they were able to walk without a break. Medical parameters at the time of listing [e.g. peak oxygen consumption (peakVO2); the German Transplant Society Score (GTSS)] were provided by Eurotransplant. Almost 50% of patients engaged in activities of daily living (housework, walking), but <10% engaged in regular exercise. All physical activity measures correlated significantly with peakVO2 (Ps < 0.01). Elevated depression scores were present in 39% of patients. Controlling for confounding variables (e.g. peakVO2, diastolic blood pressure, GTSS, age), depressive symptomatology accounted for additional variance in all physical activity measures (Ps < 0.05). The association of depressive symptoms with reduced physical activity suggests two important perspectives: attempts to increase physical activity (especially in the area of daily living) might benefit from targeting depression, and increased physical activity might also help to reduce depressive symptoms.