Brain Advance Access published online on July 10, 2008
Brain, doi:10.1093/brain/awn143
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Response to ‘The pulmonary first-pass effect, xenotransplantation and translation to clinical trials’
Department of Neurology, Stroke and Stem Cell Laboratory, Seoul National University Hospital, Seoul, South Korea
Correspondence to:
Jae-Kyu Roh, Department of Neurology, Seoul National University Hospital, 28, Yongon-dong, Chongro-gu, Seoul 110-744, South Korea E-mail: rohjk{at}snu.ac.kr
Received June 11, 2008. Accepted June 11, 2008.
Sir, we appreciate Dr Harting and colleagues for their praise and interests in our paper. The pulmonary first-pass effect of injected stem cells (lung trapping) has been issued in designing various clinical trials of intravascular stem cell transplantation (Palmieri et al., 2004
). The intravenously injected stem cells are trapped initially in the lungs and seem to escape from them to be redistributed in the systemic organs later. In rodents, intravenously injected mesenchymal stem cells (MSCs) or peripheral blood stem cells (PBSCs) accumulated initially in the lungs when observed at 5, 15 or 60 min after the injections (Gao et al., 2001; Daldrup-Link et al., 2004; Schrepfer et al., 2007), and gradually moved to liver, spleen, kidney and bone marrow for 48 h (Gao et al., 2001; Daldrup-Link et al., 2004). Pulmonary accumulation of MSCs was 50–60% in 1 h after the injection and decreased afterward to about 30% even at 3 h after the injection (Rochefort et al., 2005). In humans, intravenously injected PBSCs show a high lung uptake at 30 min (Kang et al., 2006), and the initial lung uptake was cleared away after 2 h (Kang et al., 2006). At 4 h after the injection, the distributions of the intravenously injected PBSCs were 42.12% in spleen, 21.3% in liver and only 5.8% in lung (Kang et al., 2006). Thus, the high initial pulmonary accumulation of the injected stem cells, as observed by Dr Harting and colleagues, is not surprising and the final distribution of injected stem cells should be investigated over a longer time period. In our previous observation, the splenic accumulation of the injected neural stem cells (NSCs) in the ICH rats at 3 days after the injection is likely to have been further enhanced by the splenic inflammation induced by ICH (Lee et al., 2008), as like that 25–50% of intravenously injected NSCs reach the lymph nodes of mice with experimental autoimmune encephalomyelitis (Einstein et al., 2007). We would also like to correct the comment of Dr Harting and colleagues that 
20x NSCs reached the spleen compared with the lung in our experiment. Our data were 2–3 NSCs per high power field (HPF) of lung, and 20–30 cells per HPF of splenic marginal zone (10x) (Lee et al., 2008). Because the marginal zone covers about 30% of spleen, the density can be converted into about 6–9 cells per HPF of total spleen (3x). The volumes of spleen and lung should be further multiplied in.
The issue regarding to the immune rejection after xenotransplantation is also a long time issue among the stem cell researchers. We showed that splenectomy ameliorated the effect of intravenously injected NSCs, and NSCs suppressed the in vitro macrophage activation (Lee et al., 2008). Splenectomized rats are still immune competent. If the anti-inflammatory effect of NSC was from some kinds of rejection-mediated effects, splenectomy could not have ameliorated the anti-inflammatory effects (Lee et al., 2008). In addition, NSCs could not have inhibited the in vitro macrophage activation in the culture condition without T and B cells (Lee et al., 2008). Because allogenic NSCs were also effective to reduce cerebral inflammation (Lee et al., 2008), this phenomenon is not specific to xenotransplantation. In vitro immunosuppressive effects of allogenic NSCs were also reported in other studies (Pluchino et al., 2005; Einstein et al., 2007). Accordingly, NSCs have immune modulation effect per se.
Primary rodent neurosphere cells express low levels of MHC class I, and costimulatory molecules CD80/86 interacting with T cells (Imitola et al., 2004). Small proportion of human NSCs express MHC class I molecules, but did not express MHC class II (Ubiali et al., 2007). Sometimes, human NSCs express small proportion of HLA-DQ, but no MHC I and HLA-DR (Al Nimer et al., 2004). Although human NSCs elicit low but not negligible allogenic and xenogenic immune responses (Ubiali et al., 2007), the marginal expressions of MHC class I/II prevent NSCs from to be killed by T and NK cells (Mammolenti et al., 2004). Thus, without immunosuppression, human NSCs are partially rejected from the rodent brain and thus can still survive (Wennersten et al., 2006). In contrast, allogenic MSC are completely rejected from the rat brain in 14 days (Coyne et al., 2006). Comparison of MSC, fibroblast and astrocyte grafts revealed that mesenchymal derivatives, MSC and fibroblasts, elicited inflammation and were rapidly rejected, whereas neuroectodermal astrocytes demonstrated robust survival in the absence of inflammation (Coyne et al., 2007). Given the immunosuppressive effect and low immonogenicity, NSCs seem to be somewhat resistant to the rejection phenomenon. Nevertheless, as Dr Harting and colleagues suggested, this issue needs to be solved before planning any clinical trials using NSCs.
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