Brain Advance Access published online on July 10, 2008
Brain, doi:10.1093/brain/awn142
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The pulmonary first-pass effect, xenotransplantation and translation to clinical trials—a commentary
Department of Pediatric Surgery, University of Texas Medical School at Houston, Houston, TX, USA
Correspondence to:
Matthew T. Harting or Charles S. Cox, Jr, MD, 6431 Fannin St, Houston, TX 77030, USA E-mail: matthew.t.harting{at}uth.tmc.edu or charles.s.cox{at}uth.tmc.edu
Received May 20, 2008. Accepted June 11, 2008.
Sir, we read with great interest the article by Lee and colleagues (2008
) on the effects of intravenous (IV) human neural stem cell (NSC) transplantation after intracerebral haemorrhage (ICH) in a rat model, and congratulate them on their work. The authors found that early (2 h after ICH) IV NSC (5 x 105 cells) therapy led to immediate and sustained improvements in neurologic deficits (modified limb placing test). Concomitantly, decreases in cerebral oedema, apoptosis and inflammation were identified. Most notably, the cellular biodistribution studies revealed 
20x the number of cells in the spleen as the lung. The authors went on to show that cell–cell interaction of NSCs and macrophages in the spleen may play a significant role in the anti-inflammatory mechanism of IV NSC-mediated behavioural recovery after ICH.
This seminal body of work thoroughly explores and extends previous experimentation (Pluchino et al., 2005), noting numerous cells in the spleen and identifying the potentially critical role of the spleen and splenic-derived immune cells in the anti-inflammatory response. There are several details in this model and the resulting experimental findings that piqued our interest. We have been studying the interactions between intravenously infused cells [including NSCs, mesenchymal stromal cells (MSC) and non-adherent cell populations, such as the mononuclear cell fraction (MNC Fx)] and the pulmonary microvasculature. Specifically, we have noted significant (90–95%) cell trapping in the pulmonary microvasculature (termed the pulmonary first-pass effect) among so called ‘adherent’ cell populations. We have identified the magnitude of this effect using a number of methods including infrared cell tracking with macroscopic imaging and IV delivery followed by intra-arterial sampling and subsequent flow cytometry to identify transplanted cells traversing the lungs. Adhesion molecule expression and cell size are likely to be critical determinants of this phenomenon. We have found most NSC populations to be between 14 and 19 µm in diameter (just smaller than MSC's); making pulmonary passage difficult. Although some groups have shown a lower proportion of NSC's trapped in the pulmonary circulation (Einstein et al., 2007) other cells of the same size have a significantly less efficient passage (Tolar et al., 2006). This is of particular interest to those of us involved in early clinical trial design using cellular therapy (Harting et al., 2008). What is it about NSCs that may allow a rapid, high percentage passage through the pulmonary microvasculature?
We are also keenly interested in the issue of immune rejection in heterologous cellular transplantation. In this work, the authors performed a xenotransplantation, infusing human foetal NSCs into a rodent model, without immunosuppression. While this seems to be common practice in laboratory experimentation, evidence of homologous progenitor/stem cell rejection (Coyne et al., 2006; Badillo et al., 2007) (let alone heterologous) exists. Is it possible that some magnitude of the immune modulation is related to rejection-mediated events? Despite the fact that the authors used human fibroblasts as controls (which did lead to a decrease in cerebral oedema as well, although not statistically significant; and were not used as controls in the inflammation studies), there may be more extensive immune-mediated mechanisms at play. Additionally, questions are being raised about the functional differences between human and non-human cells. We have begun using an autologous rodent bone marrow extraction/re-infusion method for stroke/traumatic brain injury models, with the hope of clarifying the immune-privileged status of these cell populations. Again, such information is critical to safe and evidence-based clinical trial design. As we move toward translating these data, the cell therapy community must explore the relative effects of xenotransplantation versus effects of cell therapy.
References
Badillo AT, Beggs KJ, Javazon EH, Tebbets JC, Flake AW. Murine bone marrow stromal progenitor cells elicit an in vivo cellular and humoral alloimmune response. Biol Blood Marrow Transplant (2007) 13:412–22.[CrossRef][Web of Science][Medline]
Coyne TM, Marcus AJ, Woodbury D, Black IB. Marrow stromal cells transplanted to the adult brain are rejected by an inflammatory response and transfer donor labels to host neurons and glia. Stem Cells (2006) 24:2483–92.[CrossRef][Web of Science][Medline]
Einstein O, Fainstein N, Vaknin I, Mizrachi-Kol R, Reihartz E, Grigoriadis N, et al. Neural precursors attenuate autoimmune encephalomyelitis by peripheral immunosuppression. Ann Neurol (2007) 61:209–18.[CrossRef][Web of Science][Medline]
Harting MT, Baumgartner JE, Worth LL, Ewing-Cobbs L, Gee AP, Day MC, et al. Cell therapies for traumatic brain injury. Neurosurg Focus (2008) 24:E18.[Medline]
Lee ST, Chu K, Jung KH, Kim SJ, Kim DH, Kang KM, et al. Anti-inflammatory mechanism of intravascular neural stem cell transplantation in haemorrhagic stroke. Brain (2008) 131:616–29.
Pluchino S, Zanotti L, Rossi B, Brambilla E, Ottoboni L, Salani G, et al. Neurosphere-derived multipotent precursors promote neuroprotection by an immunomodulatory mechanism. Nature (2005) 436:266–71.[CrossRef][Medline]
Tolar J, O'Shaughnessy MJ, Panoskaltsis-Mortari A, McElmurry RT, Bell S, Riddle M, et al. Host factors that impact the biodistribution and persistence of multipotent adult progenitor cells. Blood (2006) 107:4182–8.
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