Abstract-The discovery of bone marrow-derived endothelial progenitors in the peripheral blood has promoted intensive studies on the potential of cell therapy for various human diseases. Accumulating evidence has suggested that implantation of bone marrow mononuclear cells effectively promotes neovascularization in ischemic tissues. It has also been reported that the implanted cells are incorporated not only into the newly formed vessels but also secrete angiogenic factors. However, the mechanism by which cell therapy improves tissue ischemia remains obscure. We enrolled 29 "no-option" patients with critical limb ischemia and treated ischemic limbs by implantation of peripheral mononuclear cells. Cell therapy using peripheral mononuclear cells was very effective for the treatment of limb ischemia, and its efficacy was associated with increases in the plasma levels of angiogenic factors, in particular interleukin-1␤ (IL-1␤). We then examined an experimental model of limb ischemia using IL-1␤-deficient mice. Implantation of IL-1␤-deficient mononuclear cells improved tissue ischemia as efficiently as that of wild-type cells. Both wild-type and IL-1␤-deficient mononuclear cells increased expression of IL-1␤ and thus induced angiogenic factors in muscle cells of ischemic limbs to a similar extent. In contrast, inability of muscle cells to secrete IL-1␤ markedly reduces induction of angiogenic factors and impairs neovascularization by cell implantation. Implanted cells do not secret angiogenic factors sufficient for neovascularization but, instead, stimulate muscle cells to produce angiogenic factors, thereby promoting neovascularization in ischemic tissues. Further studies will allow us to develop more effective treatments for ischemic vascular disease. Key Words: angiogenesis Ⅲ interleukins Ⅲ muscles P eripheral vascular disease (PVD), mainly caused by atherosclerosis, leads to obstruction of the blood supply to the lower or upper extremities. PVD is known to affect 10% to 15% of the adult population in developed countries and is often associated with coronary artery disease. 1 Arteriosclerosis obliterans (ASO) is the most common cause of PVD affecting the lower limbs. Peripheral ischemia can also result from various types of vasculitis, including thromboangiitis obliterans (TAO) or Buerger's disease, which affects small-and medium-sized arteries and is related to tobacco use and male sex but not to other coronary risk factors. The 2 cardinal symptoms of limb ischemia are intermittent claudication and rest pain: the latter symptom occurs in patients with critical limb ischemia and coincides with ischemic ulceration and gangrene. The treatments of PVD include pharmacotherapy, percutaneous transluminal angioplasty, and vascular surgery and are chosen depending on the severity of the symptoms and the arteries involved. 2 However, as many as 50% of patients with critical limb ischemia will undergo limb amputation within 1 year because of an insufficient response to the treatments. 1,2 Recent progress in understanding t...

Probucol administered beginning 4 weeks before PTCA appears to reduce restenosis rates.

Background-Injection of bone marrow mononuclear cells has been reported to promote neovascularization of ischemic tissues effectively. We found that peripheral blood mononuclear cells were as efficient as bone marrow mononuclear cells for the treatment of limb ischemia in animals and showed that this treatment was feasible and safe in no-option patients with limb ischemia. However, the long-term outcome of such therapy has not been investigated. Methods and Results-We retrospectively analyzed the data for 42 patients who were treated between July 2002 and December 2005 by using the log-rank test, the Kaplan-Meier method, and the Cox proportional hazard model. Improvement of ischemic symptoms was observed in 60% to 70% of the patients. The annual rate of major amputation was decreased markedly by treatment. Improvement of ischemic symptoms was less marked in arteriosclerosis obliterans (ASO) patients on dialysis compared with nonhemodialysis ASO or thromboangiitis obliterans patients. Indeed, the survival rate of these patients was lower than that of nonhemodialysis ASO or thromboangiitis obliterans patients. Major adverse events such as death, major amputation, and cardiovascular events occurred mostly in ASO patients, and most of them were on dialysis. There was no significant difference in the cardiovascular event-free rate between responders and nonresponders. The survival rate of younger responders was better than that of nonresponders. Conclusions-Although this study was not placebo-controlled and these initial results were from a retrospective analysis, injection of peripheral blood mononuclear cells might be safe and potentially effective for the treatment of limb ischemia, but caution is needed when managing ASO patients on dialysis.