The molecular mechanisms by which mesenchymal stem cells (MSCs) suppress T-cell proliferation are poorly understood, and whether a soluble factor plays a major role remains controversial. Here we demonstrate that the T-cell-receptor complex is not a target for the suppression, suggesting that downstream signals mediate the suppression. We found that Stat5 phosphorylation in T cells is suppressed in the presence of MSCs and that nitric oxide (NO) is involved in the suppression of Stat5 phosphorylation and T-cell proliferation. The induction of inducible NO synthase (NOS) was readily detected in MSCs but not T cells, and a specific inhibitor of NOS reversed the suppression of Stat5 phosphorylation and T-cell proliferation. This production of NO in the presence of MSCs was mediated by CD4 or CD8 T cells but not by CD19 B cells. Furthermore, inhibitors of prostaglandin synthase or NOS restored the proliferation of T cells, whereas an inhibitor of indoleamine 2,3-dioxygenase and a transforming growth factor-␤-neutralizing antibody had no effect. Finally, MSCs from inducible NOS ؊/؊ mice had a reduced ability to suppress T-cell proliferation. Taken IntroductionBecause mesenchymal stem cells (MSCs) differentiate into osteocytes, chondrocytes, myotubes, and adipocytes, 1-3 they are expected to become a source of cells for regenerative therapy. Also, MSCs support hematopoietic stem cell engraftment 4-9 and modulate immunologic responses by unknown mechanisms. [9][10][11][12][13][14] Here, we investigated the molecular mechanisms by which MSCs suppress T-cell proliferation.Transforming growth factor-␤ (TGF-␤), hepatocyte growth factor, indoleamine 2,3-dioxygenase (IDO), and prostaglandin E2 (PGE 2 ) have been reported to mediate T-cell suppression by MSCs. [13][14][15] Specifically, neutralizing antibodies against TGF-␤ or hepatocyte growth factor, 13 an inhibitor of IDO,14 or an inhibitor of prostaglandin production reverse the inhibition of T-cell proliferation by MSCs. 15 In addition, some reports have shown that a soluble factor is the major mediator of suppression, [13][14][15][16][17] whereas some reports have demonstrated that T-cell-MSC contact is required for this suppression. [12][13][14]16,17 In the current study, we sought to resolve these conflicting results by using a mouse bone marrow-derived MSC system.One candidate soluble factor for T-cell suppression is nitric oxide (NO) because it is known to inhibit T-cell proliferation. [18][19][20][21][22][23][24][25] NO is produced by NO synthases (NOSs), of which there are 3 subtypes: inducible NOS (iNOS), endothelial NOS, and neuronal NOS. Like MSCs, it has been known that macrophages suppress T-cell proliferation. This suppression was reported to be mediated by NO inhibition of Stat5 phosphorylation. 18,19 Also, MSCs were reported to produce NO when they differentiate into chondrocytes. 26 We therefore investigated whether MSCs can produce NO and whether NO is involved in their ability to suppress T-cell proliferation. Materials and methods MaterialsN-nitro-L-a...

In vivo cell tracking by MRI can provide means to observe biological processes and monitor cell therapy directly. Immune cells, e.g., macrophages, play crucial roles in many pathophysiological processes, including organ rejection, inflammation, autoimmune diseases, cancer, atherosclerotic plaque formation, numerous neurological disorders, etc. The current gold standard for diagnosing and staging rejection after organ transplantation is biopsy, which is not only invasive, but also prone to sampling errors. Here, we report a noninvasive approach using MRI to detect graft rejection after solid organ transplantation. In addition, we present the feasibility of imaging individual macrophages in vivo by MRI in a rodent heterotopic working-heart transplantation model using a more sensitive contrast agent, the micrometer-sized paramagnetic iron oxide particle, as a methodology to detect acute cardiac rejection.cardiac rejection ͉ detection of single macrophage ͉ micrometer-sized iron oxide particle ͉ nanometer-sized iron oxide particle

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BACKGROUND:Extranodal involvement is considered a poor prognostic factor for patients with diffuse large B‐cell lymphoma (DLBCL); however, the prognostic impact of specific sites of involvement has not been fully elucidated.METHODS:The authors retrospectively analyzed 1221 patients treated uniformly with standard R‐CHOP therapy between 2003 and 2006. Patients with distinct forms of DLBCL such as intravascular lymphoma, primary effusion lymphoma, pyothorax‐associated lymphoma, primary central nervous system lymphoma, and intraocular lymphoma were also excluded. The authors evaluated 26 extranodal sites of involvement with respect to prognostic impact. The median age was 64 years (range, 15‐91 years).RESULTS:Univariate analysis revealed that patients with involvement of specific extranodal sites had significantly worse overall survival (OS) than did patients without such involvement; these sites included nasal cavity, paranasal sinus, lung, pleura, small intestine, peritoneum, liver, pancreas, stomach, spleen, adrenal gland, testis, bone, bone marrow, peripheral blood, skin, and subcutaneous tissue. Patients with Waldeyer ring involvement had significantly better OS. Multivariate analysis revealed that patients with the involvement of the pleura (P < .001), small intestine (P = .015), peritoneum (P = .002), adrenal gland (P < .001), testis (P = .005), bone marrow (P < .001), and peripheral blood (P = .002) had significantly worse OS, whereas those with Waldeyer ring involvement had significantly better OS (P = .038). Subgroup analysis with the nodal and/or Waldeyer patient group also showed prognostic impact of Waldeyer ring by multivariate analysis (relative risk, 0.3; P = .04).CONCLUSIONS:Extranodal involvement affects the prognosis of patients undergoing R‐CHOP therapy for DLBCL. Cancer 2012. © 2011 American Cancer Society.

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