Will the graft be cleared?
If cord blood can be administered into a non-preconditioned patient without fear of GVHD, then the next question arises as to whether the infused cells will actually endow some type of benefit or be rapidly cleared by the immune system. As previously mentioned, biological effects of mismatched cells, even if they are cleared by the immune system may have a beneficial role in inflammatory pathologies through exertion of a Th2 phenotype as seen in mothers being administered their mate's lymphocytes. Furthermore, even if transplanted cells are cleared by the immune system, it is known that apoptotic cells can mediate various therapeutic anti-inflammatory effects that are clinically relevant [68]. Animal models suggest that human cord blood cells may be administered for therapeutic benefit into other species, in absence of immune suppression. For example, Vendrame et al reported that administration of human cord blood into a non-immunosuppressed rat model of stroke resulted in increased neuronal survival, and interestingly decreased inflammatory infiltrates as compared to controls [69].
Fetal cells do not get cleared by maternal immune system
However, we do not believe that complete immune mediated clearing of regeneratively-important cord blood constituents occurs in the allogeneic setting. One reason for this notion comes from an interesting phenomena observed in pregnancy. It is well established that during pregnancy fetal cells enter maternal circulation [70]. While circulating CD34+ cells of fetal origin are found a percentage of women who have had children [71], in the bone marrow 100% of women who have had children were found to contain offspring-derived mesenchymal cells in their bone marrow [72]. Although some studies have correlated autoimmunity with residual lymphocytes causing a GVHD-like reaction in the mother, more careful analysis of these studies show that immune cells of fetal origin are largely outnumbered by cells of maternal origin. This is the basis for the proposition of Khosrotehrani et al that the fetal cells are actually "pregnancy associated progenitor cells" that act as allogeneic "repair cells" [73]. The authors of this hypothesis believe that these repair cells are actually migrating to the site of autoimmune damage in order to control injury and cause regeneration. The authors cite numerous examples in support of their idea, more notably, a case report of a hepatitis C patient who stopped treatment but disease relapse was not observed. Biopsy analysis demonstrated the liver parenchyma was heavily populated with cells of male origin that based on DNA polymorphism analysis were derived from a previous pregnancy more than a decade earlier [74]. Additionally, they cite reports of fetal cells differentiating into thyroid, cervix, gallbladder and intestinal epithelial cells [75-78]. Data from animal models, although scarce, supports the notion that fetal cells trafficking into the mother may play some reparative function. For example, it was reported that EGFP expressing fetal cells would selectively home into damaged maternal renal and hepatic tissues after gentamycin and ethanol induced injury [79]. Furthermore, another study demonstrated that subsequent to excitotoxic injury in the maternal brain, fetal-derived EFGP positive cells can be identified which express morphology and markers of neurons, astrocytes, and oligodendrocytes [80]. The authors of this paper are not stating that the fetal transfer of mesenchymal cells to the maternal host is an exact duplicate of an allogeneic cord blood transplant in absence of immune suppression. Rather, we are proposing fetal to maternal trafficking as a possible example of a natural biological situation in which stem cells may persist in an allogeneic environment without induction of complete tolerance.
Mesenchymal stem cells do not need myeloablation for efficacy
Currently there are several ongoing clinical trials in Phase I-III using "universal donor" mesenchymal stem cells in non-conditioned recipients for treatment of Crohn's disease [81], GVHD [82], and myocardial infarction [83]. Although these cells are bone marrow expanded mesenchymal cells, the superior proliferative potential of cord blood mesenchymal cells may allow them to not only escape immune destruction, but also expand in vivo and mediate therapeutic effects superior to those derived from the bone marrow. The fact that regulatory agencies have allowed advancement of "off-the-shelf" universal donor mesenchymal stem cells supports the numerous reports of clinical efficacy in an allogeneic setting.
Clinical evidence of cord blood efficacy in absence of myeloablation
To the knowledge of the authors, there have only been 3 published reports of non-conditioned recipients receiving cord blood cells for regenerative purposes. The first report is of 4 patients with Buerger's disease who were administered 4/6 HLA matched allogeneic cord blood cells locally in the area of limb ischemia. In all patients rest pain disappeared and necrotic lesions healed approximately 4 weeks subsequent to cell administration. Significant angiographically evidenced neoangiogenesis proximal to area of administration was observed [84]. No graft versus host, or inflammation was observed at the site of injection. The second published report is of a matrix delivered allogeneic cord blood dose to a patient who suffered from spinal cord injury. Improved sensory perception and movement was observed, as well as CT and MRI observation of tissue regeneration at site of injury was reported [85]. The third report described 2 patients with non-healing wounds who were treated with autologous fibrin glue containing matched (2 mismatches allowed) allogeneic cord blood isolated CD34+ cells. Significant wound healing was observed with no indication of GVHD at 3 and 7 months subsequent to treatment [86]. These reports give some suggestion that administration of mismatched cord blood stem cells may endow potentially therapeutic benefit without rejection, at least immediate rejection, by the host versus graft process. More importantly, these studies demonstrate that allogeneic cord blood cells may be used clinically without immune-mediated clearing before therapeutic properties are exerted.
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