Intrahepatic eosinophilic proliferative phlebitis in Japanese black cattle indicate allergies involving mast cell tryptase-dependent activation.

Cow-specific feature hepatic lesion, termed as eosinophilic proliferative phlebitis (EPP), has been mainly detected in Japanese black cattle and identified histologically eosinophilic infiltration and endothelial hyperplasia in portal areas. We previously proposed EPP as a food allergy from the pathological characteristics and a significant increase of serum immunoglobulin E specific to curly dock (Rumex crispus) in allergens testing, however, first report had regarded EPP an atypical type of bovine fascioliasis. In EPP lesions, eosinophilic infiltration was observed to the hypertrophic endothelium and not to the intrahepatic bile duct, and that was related to eotaxin-1 expression. In EPP, the mast cells increased as well as in fascioliasis, and the mast cells producing tryptase without chymase increased with interleukin-4 production. In this context, hyperplasia of periendothelium expressing proteinase-activated receptor-2 (PAR-2) and not angiotensin II was observed. Contrastably, in fascioliasis, unique mast cells producing neither tryptase nor chymase infiltrated, and the periendothelium expressed neither PAR-2 nor angiotensin II. Interestingly, EPP had not occurred liver injury with raised hepatic enzymes like fascioliasis, and suggested to a correlation with severe serum hypo-vitamin A. Overall, this study suggests that EPP is an allergic disease by main difference between adaptive immunity to allergens and innate immunity to parasites.

Morphofunctional analysis of human pancreatic cancer cell lines in 2- and 3-dimensional cultures.

Genetic, transcriptional, and morphological differences have been reported in pancreatic ductal adenocarcinoma (PDAC) cases. We recently found that epithelial or mesenchymal features were enhanced in three-dimensional (3D) cultures compared to two-dimensional (2D) cultures. In this study, we examined the differences in the morphological and functional characteristics of eight PDAC cell lines in 2D and 3D cultures. Most PDAC cells showed similar pleomorphic morphologies in 2D culture. Under 3D culture, PDAC cells with high E-cadherin and low vimentin expression levels (epithelial) formed small round spheres encircled with flat lining cells, whereas those with high vimentin and low E-cadherin expression levels (mesenchymal) formed large grape-like spheres without lining cells and were highly proliferative. In 3D culture, gemcitabine was more effective for the spheres formed by PDAC cells with epithelial features, while abraxane was more effective on those with mesenchymal features. The expression levels of drug transporters were highest PDAC cells with high vimentin expression levels. These findings indicate that PDAC cells possess various levels of epithelial and mesenchymal characteristics. The 3D-culture method is useful for investigating the diversity of PDAC cell lines and may play important roles in the development of personalized early diagnostic methods and anticancer drugs for PDAC.

Molecular characterization of free fatty acid receptors FFAR2 and FFAR3 in the domestic cat.

G protein-coupled receptors 41 and 43 were identified and characterized as free fatty acid receptors (FFAR) 3 and 2, respectively. FFAR2 and FFAR3 mediate short-chain fatty acids (SCFAs) as signalling molecules. The present study aimed to give molecular characterization of FFAR2 and FFAR3 in the domestic cat. High homology with that in other mammals was revealed by cDNA cloning of cat FFAR2 FFAR3. We analyzed the tissue distribution of cat FFAR2 and FFAR3 mRNA using quantitative polymerase chain reaction. The inhibition of intracellular cAMP concentrations was observed in cells transfected with cat FFAR2 or FFAR3 and treated with SCFAs. The activation of nuclear factor of activated T cells-luciferase reporter was only observed in cat FFAR2 transfected cells but not in FFAR3. Split luciferase assay (NanoLuc Binary Technology; NanoBiT) for FFAR2 or FFAR3 and Arrestin-3/ß-arrestin-2 revealed acetate-/propionate-induced recruitment to cat FFAR2 or FFAR3 in CHO-K1 cells. Our results indicate that FFAR2 and FFAR3 are functional receptor proteins that are expressed in cat tissues and show differential distribution patterns.

Low expression of a Ddm7/Ldm7-hybrid mutant (D/Ldm7) in the novel haplotype H-2nc identified in atopic dermatitis model NC/Nga mice.

Environmental factors and the major histocompatibility complex (MHC) are involved in the pathogenesis of atopic dermatitis (AD). However, MHC type (H2 haplotype) of AD model mice NC/Nga is poorly understood. Alloreactive CD8+ or CD4+ T cells in NC/Nga strongly responded to each antigen-presenting cells (A/J: H-2a, C57BL/6: H-2b, BALB/c: H-2d, or C3H/HeJ: H-2k), suggesting that NC/Nga has other H2 haplotype. Polymorphic microsatellite (CA)n repeats in TNF-α gene differ based on the H2 haplotype at present. NC/Nga's (CA)n repeats (n = 19) were different from other examined strains, A/J (n = 14), BALB/c (n = 14), C3H/HeJ (n = 16), and C57BL/6 (n = 20). Using flow cytometry and genotyping, we demonstrated the NC/Nga H2 haplotype had a unique phenotype (Kd, I-Ak, and I-Ek) in which Dd and Ld lacked as protein despite sensitive mRNA detection. The loss of Dd and Ld was caused by forming a unique Ddm7/Ldm7-hybrid mutant (D/Ldm7). We propose to call this novel H2 haplotype the "H-2nc," and provide the important information regarding the AD research using NC/Nga mice.

The Role of Proteasome Inhibitor MG132 in 2,4-Dinitrofluorobenzene-Induced Atopic Dermatitis in NC/Nga Mice.

BACKGROUND: Although immunosuppressants for therapy of atopic dermatitis (AD) are still being sought, proteasome inhibitors are also potential candidates for the treatment of AD. Proteasome inhibitors exert various effects by blocking proteasomal degradation and help regulate processes such as apoptosis induction via caspase-9, cell cycle progression via cyclins, NF-κB inactivation via IκB, and downregulation of antigen cross-presentation. The cells targeted by proteasome inhibitors are therefore activated cells undergoing proliferation or differentiation, and antigen-presenting cells carrying out protein degradation. OBJECTIVES: This study investigated the therapeutic effects and side effects of a proteasome inhibitor, MG132, on the treatment of AD. METHODS: AD-like disease in NC/Nga mice housed under specific pathogen-free conditions was induced by repeated application of 2,4-dinitrofluorobenzene (DNFB). Disease progression was evaluated by inflammation score, histopathology, and serum IgE level, and the effects of systemic MG132 administration were investigated. The percentages and absolute numbers for each population of Th1, Th2, and Th17 cells in the axillary lymph nodes were analyzed by flow cytometry. RESULTS: DNFB application increased the expression of a unique major histocompatibility complex class I mutant molecule D/Ldm7 in dendritic cells (DCs), and increased Th1 and Th17 cells in NC/Nga mice. In vivo MG132 administration to NC/Nga mice with DNFB-induced dermatitis reduced Th17 cells but maintained the level of Th1 cells, resulting in the alleviation of dermatitis lesions by decreasing both serum IgE hyperproduction and mast cell migration. To understand the mechanisms maintaining Th1 cell levels following in vivo MG132-administration, we focused on the role of proteasomes regulating D/Ldm7 expression. Interestingly, 20S proteasome activity was higher in NC/Nga DCs than in BALB/c DCs. In vitro MG132 administration partially increased D/Ldm7 expression in a dose-dependent manner during DC maturation, and induced IFN-γ production from autoreactive CD8+ T cells but not from CD4+ T cells following coculturing with D/Ldm7-upregulated DCs. CONCLUSION: Although MG132 administration temporarily alleviated AD pathogenesis in NC/Nga mice, prolonged MG132 treatment may result in immunopathogenesis leading to chronic AD due to its side effect of maintaining Th1 levels via autoreactive CD8+ T cells.

Signs of atopic dermatitis and contact dermatitis affected by distinct H2-haplotype in the NC/Nga genetic background.

We recently advocated in favour of naming a novel H2-haplotype consisting of Kd, D/Ldm7, I-Ak and I-Ek in the atopic dermatitis (AD) mouse model NC/Nga as "H-2nc." The role of the H2-haplotype in AD development was investigated in H2 b -congenic NC/Nga mice (NC.h2 b/b and NC.h2 b/nc ) established by backcrossing. A severe 2,4-dinitrofluorobenzene (DNFB)-induced dermatitis in NC/Nga was alleviated partially in NC.h2 b/nc and significantly in NC.h2 b/b . The AD phenotype was correlated with thymic stromal lymphopoietin (TSLP)-epidermal expression levels and serum levels of total IgE and IL-18/IL-33. Histologically, allergic contact dermatitis (ACD) was accompanied by lymphocytes and plasma cells-infiltrating perivasculitis in NC.h2 b/nc and NC.h2 b/b and clearly differed from AD accompanied by neutrophils, eosinophils and macrophages-infiltrating diffuse suppurative dermatitis in NC/Nga. Interestingly, IFN-γ/IL-17 production from autoreactive CD4+ T-cells remarkably increased in DNFB-sensitised NC.h2 b/b but not in NC/Nga. Our findings suggest that AD or ACD may depend on haplotype H-2nc or H-2b, respectively, in addition to the NC/Nga genetic background.

Clonal deletion of T cell repertoires with specific T cell receptor Vß chains by two endogenous superantigens in NC/Nga mice.

Superantigens (SAgs) are powerful T-cell stimulatory proteins. Because an atopic dermatitis (AD) model NC/Nga mice had two endogenous SAgs, namely minor lymphocyte-stimulating locus-1a (Mls-1a) and mouse mammary tumor virus (MMTV)(SHN), SAg-responsive T-cells bearing Vß5.1, Vß6, Vß8.1, Vß8.2, Vß8.3, Vß9, and Vß11 should be endogenously deleted. Here, we discuss that the endogenous SAgs-expression may be involved in AD-sensitivity in NC/Nga mice.

Effect of Gonadectomy on the Androgen-Dependent Behavior of Ganglion Cell-Like Cells in Djungarian Hamsters (Phodopus sungorus).

Ganglion cell-like (GL) cells reside in the dermis of the ventral skin of mature male Djungarian hamsters (Phodopus sugorus) and express androgen receptor (AR). To assess whether GL cells have androgen-dependent behavior, we evaluated the histologic changes of GL cells after gonadectomy. Five male and 5 female hamsters were gonadectomized at the age of 4 wk and necropsied 14 wk later. The number, distribution, and proliferative activity of GL cells in the thoracoabdominal and dorsal skins were evaluated histologically and compared with those of corresponding intact animals. GL cells were more numerous, were distributed throughout the skin more widely, and had higher proliferative activity in the intact male hamsters than in their gonadectomized counterparts. Similar trends regarding these 3 parameters were seen in ovariectomized compared with intact female hamsters and between intact male and intact female hamsters. These results suggest that the GL cells of Djungarian hamsters demonstrate sex-associated differences in their distribution and proliferative activity and that androgen may be involved in the development of these cells.

Histopathologic and immunohistochemical features of soft palate muscles and nerves in dogs with an elongated soft palate.

OBJECTIVE: To histologically evaluate and compare features of myofibers within the elongated soft palate (ESP) of brachycephalic and mesocephalic dogs with those in the soft palate of healthy dogs and to assess whether denervation or muscular dystrophy is associated with soft palate elongation. SAMPLE: Soft palate specimens from 24 dogs with ESPs (obtained during surgical intervention) and from 14 healthy Beagles (control group). PROCEDURES: All the soft palate specimens underwent histologic examination to assess myofiber atrophy, hypertrophy, hyalinization, and regeneration. The degrees of atrophy and hypertrophy were quantified on the basis of the coefficient of variation and the number of myofibers with hyalinization and regeneration. The specimens also underwent immunohistochemical analysis with anti-neurofilament or anti-dystrophin antibody to confirm the distribution of peripheral nerve branches innervating the palatine myofibers and myofiber dystrophin expression, respectively. RESULTS: Myofiber atrophy, hypertrophy, hyalinization, and regeneration were identified in almost all the ESP specimens. Degrees of atrophy and hypertrophy were significantly greater in the ESP specimens, compared with the control specimens. There were fewer palatine peripheral nerve branches in the ESP specimens than in the control specimens. Almost all the myofibers in the ESP and control specimens were dystrophin positive. CONCLUSIONS AND CLINICAL RELEVANCE: These results suggested that palatine myopathy in dogs may be caused, at least in part, by denervation of the palatine muscles and not by Duchenne- or Becker-type muscular dystrophy. These soft palate changes may contribute to upper airway collapse and the progression of brachycephalic airway obstructive syndrome.

Investigation of the roles of fascioliasis and food allergy in intrahepatic eosinophilic proliferative pylephlebitis in Japanese Black cattle.

Intrahepatic eosinophilic proliferative pylephlebitis (EPP) in Japanese Black (JB) cattle generally has been considered to be an atypical form of fascioliasis. However, there are many cases of EPP in which no Fasciola spp. have been detected in the livers of affected cattle. The aims of this study were to ascertain the relationship between EPP and hepatic fascioliasis and to investigate the role of food allergy in the disease. Histologically, EPP lesions were characterised by severe endothelial proliferation of the interlobular veins, accompanied by varying degrees of fibrosis and eosinophilic infiltration in portal areas, which could be differentiated from chronic cholangiohepatitis, the typical lesion of hepatic fascioliasis. In addition to hepatic lesions, all cases of EPP had varying degrees of eosinophilic infiltration in the perilymphoid red pulp of the spleen, whereas both affected and unaffected animals had eosinophilic infiltrates in the mucosa of the small intestine. Antibodies against Fasciola spp. were detected in 1/14 EPP cases by ELISA; the seropositive case had EPP in combination with chronic cholangitis. There was no significant difference in total concentration of IgE between cases of EPP and unaffected cattle. Serum IgE levels specific to curly dock (Rumex crispus) and oats (Avena sativa) were higher in EPP cases than in unaffected cattle by allergen profiling screening testing and ELISA. The results of this study suggest that hepatic fascioliasis is unlikely to be the cause of EPP in JB cattle and that food allergens should be investigated as possible aetiological agents.

Cutaneous invasive micropapillary carcinoma of probable apocrine sweat gland origin in a cat.

An invasive micropapillary carcinoma (IMC) occurred in the buccal skin of an 18-year-old female cat. Histologically, the tumor had a honeycomb pattern characterized by clusters of neoplastic epithelial cells that were surrounded by empty clear spaces and lined with fibrocollagenous stroma. On immunohistochemistry, the neoplastic cells were positive for cytokeratin (clone CAM5.2; pancytokeratin, clone AE1/AE3) and carcinoembryonic antigen (CEA) but negative for cytokeratin 14, vimentin, S100, smooth muscle actin, and p63. The CEA-positive staining reaction was present along the outermost rim of the neoplastic cell clusters consistent with an "inside-out" immunoreactivity pattern. Examination of the tumor cells by electron microscopy revealed microvilli on the outermost rim of neoplastic cells that were directed toward the surrounding vacant space. Based on histomorphological characteristics, the neoplasm was defined as an IMC of "pure-type." The location site and immunohistochemical features suggest the tumor was most likely derived from the apocrine sweat glands in the buccal skin.

Appearance and distribution of stromal myofibroblasts and tenascin-C in feline mammary tumors.

Myofibroblasts and extracellular matrix protein tenascin-C (Tn-C) are known to be implicated in cancer progression in human cancer. In feline mammary tumors that are a suitable model for human breast cancer, however, little is known about stromal myofibroblasts and no information is available on the expression of Tn-C. Feline samples of normal mammary glands and proliferating mammary lesions were routinely processed and serial sections were cut and immunostained with anti-α-smooth muscle actin (α-SMA) or Tn-C antibody. Myofibroblasts were not included in the stroma of 90% (9/10) of normal mammary gland tissues, 92% (12/13) of adenosis, and 63% (5/8) of simple adenomas. On the other hand, all 40 simple carcinomas contained stromal myofibroblasts to a varied extent. Tn-C expression was detected in the stroma of 92% (37/40) of carcinomas, and its global distribution almost coincided with that of myofibroblasts. In addition, Tn-C immunoreactivity was occasionally observed in the basement membrane zone around ducts in some cases of normal mammary glands and benign lesions, but barely observed in the stroma. These results suggest that stromal myofibroblasts may be a major cellular source of Tn-C and be involved in malignant progression of feline mammary tumor.

Adjuvant effects of formalin-inactivated HSV through activation of dendritic cells and inactivation of myeloid-derived suppressor cells in cancer immunotherapy.

Use of adequate adjuvant is necessary for induction of effective antitumor immune responses. To develop an effective adjuvant for cancer immunotherapy, we selected formalin-inactivated (f)-HSV as an adjuvant component, and analyzed the mechanisms underlying its adjuvant effects. First, we found that f-HSV can induce the tumor antigen-specific CTLs by enhancing antigen cross-presentation by dendritic cells (DCs), mainly through TLR2, but not TLR9. Next, f-HSV was also found to prevent the accumulation of myeloid-derived suppressor cells (MDSCs). We demonstrated that the expansion of MDSCs in the blood and spleen during tumor progression required B cells producing the inflammatory angiogenesis factors, vascular endothelial growth factor (VEGF)-A and neuropilin-1 (NRP-1), a co-receptor for VEGF receptor-2 (VEGFR-2). Interestingly, the transmembrane-type NRP-1 on B cells changed to soluble-type NRP-1 (sNRP-1) by f-HSV treatment. We further showed that the sNRP-1 and VEGF-A secreted from B cells by f-HSV treatment could abrogate the immunosuppressive ability of MDSCs. These results suggest that f-HSV can enhance antitumor immune responses as an adjuvant, not only through activation of DCs, but also inactivation of MDSCs via B cells.

Characterization of spheres derived from canine mammary gland adenocarcinoma cell lines.

There is increasing evidence for the presence of cancer stem cells in several solid tumors, and these cancer stem cells have a potential role in tumor initiation, aggression, and recurrence. The stem cell-like properties of spheres derived from canine mammary tumors remain largely elusive. We attempted to induce sphere formation using four cell lines of canine mammary adenocarcinoma, and characterized the spheres derived from a CHMp line in vitro and in vivo. The CHMp-derived spheres showed predominantly CD44+CD24- population, higher expression of stem cell-related genes, such as CD133, Notch3 and MDR, and higher resistance to doxorubicin compared with the CHMp-derived adherent cells. Xenograft transplantations in nude mice demonstrated that only 1 × 10(4)sphere cells were sufficient for tumor formation. Use of the sphere assay on these sphere-derived tumors showed that sphere-forming cells were present in the tumors, and were maintained in serial transplantation. We propose that spheres derived from canine mammary adenocarcinoma cell lines possess a potential characteristic of cancer stem cells. Spheres derived from canine mammary tumors could be a powerful tool with which to investigate novel therapeutic drugs and to elucidate the molecular and cellular mechanisms that underlie tumorigenesis.

Lipid-rich carcinoma in the mammary gland of a Djungarian hamster (Phodopus sungorus).

A lipid-rich carcinoma of the mammary gland was diagnosed in a female Djungarian hamster (Phodopus sungorus), which was kept as an indoor pet. The animal underwent surgery for a primary tumor arising in the mammary gland at the age of 16 months, and also for a recurrent tumor 6 months later. Histologically, the primary neoplasm was composed of 2 different cell populations: nonvacuolated glandular neoplastic cells with moderate atypia, and vacuolated neoplastic cells with marked atypia. Transition from the nonvacuolated glandular cells to the vacuolated cells was frequently seen. The recurrent neoplasm was composed predominantly of vacuolated neoplastic cells that often invaded the surrounding soft tissue. The cytoplasmic vacuoles contained neutral lipids, as confirmed by oil red O and Nile blue staining. The vacuolated neoplastic cells were immunopositive for cytokeratin and negative for vimentin, alpha-smooth muscle actin, p63, estrogen receptor alpha, and androgen receptor. Presumably, this high-grade, lipid-rich mammary carcinoma had developed from a low-grade mammary adenocarcinoma.

Primary neuroblastoma in the skin of an adult shih tzu dog.

A subcutaneous mass arising in the right gluteal area of an 11-year-old female shih tzu dog was surgically excised. Histologically, the mass was composed of small round or ovoid neoplastic cells that were arranged in nests of various sizes. The neoplastic cells generally had hyperchromatic nuclei and scanty eosinophilic cytoplasm, and were surrounded by a pale pink fibrillar area. Immunohistochemically, the neoplastic cells were positive for vimentin, S-100 protein, neurone-specific enolase and synaptophysin, but negative for cytokeratin, neurofilament protein, glial fibrillary acidic protein and chromogranin A. On ultrastructural observation, aggregates of thin cytoplasmic processes were frequently seen among the neoplastic cells. Based on these features, the tumour was diagnosed as a neuroblastoma. To the authors' knowledge, this is the first description of a neuroblastoma originating from the skin in an adult dog.

Targeted inhibition of IL-10-secreting CD25- Treg via p38 MAPK suppression in cancer immunotherapy.

Cancer-induced immunotolerance mediated by inducible Treg (iTreg) is a major obstacle to cancer immunotherapy. In a basic study of immunotolerance, injection of an endogenous superantigen, i.e. the minor lymphocyte stimulatory (Mls)-1(a), into specific TCR Vbeta8.1-Tg mice enabled generation of anergic CD25(-) iTreg, the immunosuppressive function of which was maintained by IL-10 production via p38-MAPK activation. Interestingly, although p38-chemical inhibitor (p38-inhibitor) is capable of breaking CD25(-) iTreg-induced immunotolerance, the p38-inhibitor had hardly any immunotolerance breaking effect when CD25(+) Treg were present, suggesting that depletion of CD25(+) Treg is necessary for p38-inhibitor to be effective. Peptide OVA(323-339) iv.-injection into its specific TCR-Tg (OT-II) mice also induced adaptive tolerance by iTreg. Peptide immunotherapy with p38-inhibitor after CD25(+) Treg-depletion was performed in an OVA-expressing lymphoma E.G7-bearing tolerant model established by adoptive transfer of OT-II CD25(-) iTreg, which resulted in suppression of tumor growth. Similarly, the antitumor immunity induced by peptide immunotherapy in colon carcinoma CT26-bearing mice, in which the number of IL-10-secreting iTreg is increased, was augmented by treatment with p38-inhibitor after CD25(+) Treg-depletion and resulted in inhibition of tumor progression. These results suggest that simultaneous inhibition of two distinct Treg-functions may be important to the success of cancer immunotherapy.

Identification of HLA-A2- and A24-restricted T-cell epitopes derived from SOX6 expressed in glioma stem cells for immunotherapy.

Malignant gliomas are the most aggressive human primary brain tumors and are currently incurable. Immunotherapies have the potential to target glioma and glioma stem cells (GSCs) that are resistant to conventional therapies. We previously identified SOX6 as a human glioma antigen and demonstrated that vaccination with SOX6 DNA induced cytotoxic T lymphocytes (CTLs) specific for glioma, thereby exerting therapeutic antitumor responses in glioma-bearing mice. In this study, we attempted to identify SOX6-derived peptides as specific targets for effective and safe T-cell-mediated immunotherapy targeting SOX6-positive glioma and GSCs. In vitro stimulation with human leukocyte antigen (HLA)-A*2402 (A24)-restricted peptides, RFENLGPQL (SOX6(504)) and PYYEEQARL (SOX6(628)) or the HLA-A*0201 (A2)-restricted peptide, ALFGDQDTV (SOX6(447)) was capable of inducing SOX6 peptide-specific CTLs in peripheral blood mononuclear cells derived from healthy donors and glioma patients. These CTLs were able to lyse a majority of glioma cell lines and a GSC line derived from human glioblastoma in an HLA Class I-restricted and an antigen-dependent manner. Furthermore, peptide vaccines of SOX6(628), which was conserved in the murine SOX6 protein and expected to bind to major histocompatibility complex (MHC) H-2(d), induced CTLs specific for SOX6(628) in H-2(d) mice. Normal autologous cells from mice, in which SOX6-specific immune responses were generated, were not destroyed. These results suggest that these SOX6 peptides are potnetially immunogenic in HLA-A24 or -A2 positive glioma patients and should be considered as a promising strategy for safe and effective T-cell-based immunotherapy of patients with gliomas.

Transplantation of dendritic cells promotes functional recovery from spinal cord injury in common marmoset.

We previously reported that implantation of dendritic cells (DCs) into the injured site activates neural stem/progenitor cells (NSPCs) and promotes functional recovery after spinal cord injury (SCI) in mice. Working toward clinical application of DC therapy for SCI, we analyzed whether DCs promote functional recovery after SCI in a non-human primate, the common marmoset (CM). CMs are usually born as dizygotic twins. They are thus natural bone marrow and peripheral blood chimeras due to sharing of the placental circulation between dizygotic twins, leading to functional immune tolerance. In this study, to identify adequate CM donor-and-host pairs, mixed leukocyte reaction (MLR) assays were performed. Then, CM-DCs were generated from the bone marrow of the twin selected to be donor and transplanted into the injured site of the spinal cord of the other twin selected to be host, 7 days after injury. Histological analyses revealed fewer areas of demyelination around the injured site in DC-treated CMs than in controls. Immunohistochemical analysis showed that more motor neurons and corticospinal tracts were preserved after SCI in DC-treated CMs. Motor functions were evaluated using three different behavior tests and earlier functional recovery was observed in DC-treated CMs. These results suggest DC therapy to possibly be beneficial in primates with SCI and that this treatment has potential for clinical application.