gms | German Medical Science

Einleitung: The treatment of vascular occlusive disease is of tremendous clinical importance for alleviation of morbidity and mortality in the Western World. Although spontaneous endogenous collateral growth bypasses local stenosis thereby attenuating local tissue ischemia and improving clinical outcome, the net effect is rarely adequate to fully compensate for the flow lost to occlusion of the native artery. At the moment therapeutic options are aterio-venous-bypasses and percutaneous transluminal angioplasty, effective methods to restore vascular perfusion. However, these methods are associated with 20% restenosis during the first year. Furthermore, these therapeutic strategies are of limited use for severe and diffuse disease. Therefore, therapeutic enhancement of collateral growth holds great promise for the alleviation of vascular occlusive disease. Our group has been focusing on cell therapeutic approaches. Monocytes (Mo), for example, play a key role for the remodeling of a pre-existing arteriole into a collateral artery. They home to sites of collateral vessel growth and release multiple cytokines thereby promoting collateral vessel growth.We have tested whether their homing capacity can be exploited for a therapeutic approach by ex vivo engineering a re-transplantation for an augmentation of arteriogenesis.

Material und Methoden: Rabbit Mo were isolated by Ficoll-Paque and cultured in macrophage-medium containing GM-CSF (200 U/ml) for 24 h. 30 Mio. Mo were i.v. injected into rabbits 24 hours after ligation of their femoral artery. 7 days later maximal adenosine-induced conductance (C= flow/mean arterial pressure - mean peripheral pressure, ml/min/100 mmHg) was determined using an ultrasonic flow probe placed around the external iliac artery. Additionally, collateral arteries (ca) within the hind limb were angiographically quantified.

Ergebnisse: Transplantation of allogenic monocytes (alMo, same species) resulted in a strong promotion of arteriogenesis (C= 192±18, ca= 16±1, p<0.001) most likely through induction of local inflammation and recruitment of recipient monocytes, transplantation of autologous cells (auMo same animal) was not able to significantly augment collateralization. (C= 130±29, ca= 11±1, n.s.) in comparison to ligation alone (C= 105±20, ca= 11±2) which was not further enhanced by their cultivation and thereby activation for up to 7 days (C= 121±15, ca= 12±2, n.s.).Despite the intriguing clinical implications, the phenomenon is hardly understood. Furthermore, transplantation of allogenic monocytes may be of substantial risk (uncontrolled immunologic reaction with subsequent shock, HIV, hepatitis).Thus we aimed auMo as vehicles for a gene therapeutic approach. Previously, our group had demonstrated the role of GM-CSF in arteriogenesis. We, therefore, infected 30 Mio auMo with an adenoviral vector coding for GM-CSF (25 pfu) 24 h prior to injection. This was able to efficiently augment arteriogenesis (C= 211±46, ca= 19±2, p<0.001) in comparison to control-transduced cells (C= 122±7, ca= 14±2) being close to values determined in unligated control vessels (C= 262±31, ca= 5±1).

Schlussfolgerung: This study has exciting clinical implications: Obtaining monocytes is currently widely available, all of which makes the ultimate goal of applying this strategy to humans for therapy of vascular disease eminently attractive.