Origin of vascular smooth muscle cells and the role of circulating stem cells in transplant arteriosclerosis

To date, clinical solid-organ transplantation has not achieved its goals as a long-term treatment for patients with end-stage organ failure. Development of so-called chronic transplant dysfunction (CTD) is now recognized as the predominant cause of allograft loss long term (after the first postoperative year) after transplantation. CTD has the remarkable histological feature that the luminal areas of intragraft arteries become obliterated, predominantly with vascular smooth muscle cells (VSMCs) intermingled with some inflammatory cells (transplant arteriosclerosis, or TA). The development of TA is a multifactorial process, and many risk factors have been identified. However, the precise pathogenetic mechanisms leading to TA are largely unknown and, as a result, adequate prevention and treatment protocols are still lacking. This review discusses the origin (donor versus recipient, bone marrow versus nonbone marrow) of the VSMCs in TA lesions. Poorly controlled influx and subsequent proliferative behavior of these VSMCs are considered to be critical elements in the development of TA. Available data show heterogeneity when analyzing the origin of neointimal VSMCs in various transplant models and species, indicating the existence of multiple sites of origin. Based on these findings, a model considering plasticity of VSMC origin in TA in relation to severity and extent of graft damage is proposed

Neonatal oral administration of DiaPep277, combined with hydrolysed casein diet, protects against Type 1 diabetes in BB-DP rats. An experimental study

Aims/hypothesis. Environmental factors such as diet and bacterial antigens play an important role in the onset of Type 1 diabetes. Different self-antigens are suggested to play a role in the development of diabetes. Antibodies against the 60-kDa heat shock protein 60, which have a high homology to bacterial heat shock protein 65, have been found in the circulation at the onset of diabetes in humans and in pre-diabetic NOD-mice. One of the immunodominant epitopes in autoimmune diabetes is p277, a specific peptide of human heat shock protein 60 corresponding to positions 437-460. In this study we investigated whether neonatal oral administration of DiaPep277 (a synthetic peptide analogue of p277) affected the development of diabetes in the BioBreeding-Diabetes Prone (BB-DP) rat, and whether this could potentiate the effect of a protective hydrolysed casein-diet. Methods. BB-DP rats were orally inoculated once per day with placebo or DiaPep277 at days 4, 5, 6 and 7 of life. At the age of 21 days rats were weaned on to a conventional, cereal-based diet or on to the hydrolysed casein-diet. Results. The development of diabetes in animals receiving DiaPep277 in combination with the hydrolysed casein-diet was delayed by 17 days, and a relative reduction of the incidence by 64% was seen. Non-diabetic animals did not show any sign of insulitis. Conclusions/interpretation. Short-term neonatal feeding with p277 in early life, combined with diet adaptation, appears to provide a procedure to significantly reduce the development of Type 1 diabetes in later life