Mesenchymal Stem Cells Ameliorate Renal Inflammation in Adriamycin-induced Nephropathy

Mesenchymal stem cells (MSCs) ameliorate the renal injury in Adriamycin (ADR)-induced nephropathy, but the mechanisms underlying their efficacy remain incompletely understood. In this study, we demonstrated that MSCs increased the survival, recovered body weight loss, and decreased proteinuria and serum creatinine levels in ADR-treated mice. MSCs also prevented podocyte damage and renal fibrosis by decreasing the expression of fibronectin, collagen 1α1, and α-smooth muscle actin. From a mechanistic perspective, MSCs inhibited renal inflammation by lowering the expression of CCL4, CCL7, CCL19, IFN-α/β, TGF-β, TNF-α, and chitinase 3-like 1. In summary, our data demonstrate that MSCs improve renal functions by inhibiting renal inflammation in ADR-induced nephropathy.

Cell-based Immunotherapy for Colorectal Cancer with Cytokine-induced Killer Cells

Colorectal cancer is the third leading cancer worldwide. Although incidence and mortality of colorectal cancer are gradually decreasing in the US, patients with metastatic colorectal cancer have poor prognosis with an estimated 5-year survival rate of less than 10%. Over the past decade, advances in combination chemotherapy regimens for colorectal cancer have led to significant improvement in progression-free and overall survival. However, patients with metastatic disease gain little clinical benefit from conventional therapy, which is associated with grade 3~4 toxicity with negative effects on quality of life. In previous clinical studies, cell-based immunotherapy using dendritic cell vaccines and sentinel lymph node T cell therapy showed promising therapeutic results for metastatic colorectal cancer. In our preclinical and previous clinical studies, cytokine-induced killer (CIK) cells treatment for colorectal cancer showed favorable responses without toxicities. Here, we review current treatment options for colorectal cancer and summarize available clinical studies utilizing cell-based immunotherapy. Based on these studies, we recommend the use CIK cell therapy as a promising therapeutic strategy for patients with metastatic colorectal cancer.

Adoptive Cell Therapy of Melanoma with Cytokine-induced Killer Cells

Melanoma is the most aggressive skin cancer and its incidence is gradually increasing worldwide. Patients with metastatic melanoma have a very poor prognosis (estimated 5-year survival rate of <16%). In the last few years, several drugs have been approved for malignant melanoma, such as tyrosine kinase inhibitors and immune checkpoint blockades. Although new therapeutic agents have improved progression-free and overall survival, their use is limited by drug resistance and drug-related toxicity. At the same time, adoptive cell therapy of metastatic melanoma with tumor-infiltrating lymphocytes has shown promising results in preclinical and clinical studies. In this review, we summarize the currently available drugs for treatment of malignant melanoma. In addition, we suggest cytokine-induced killer (CIK) cells as another candidate approach for adoptive cell therapy of melanoma. Our preclinical study and several previous studies have shown that CIK cells have potent anti-tumor activity against melanomas in vitro and in an in vivo human tumor xenograft model without any toxicity.

Preclinical Efficacy and Mechanisms of Mesenchymal Stem Cells in Animal Models of Autoimmune Diseases

Mesenchymal stem cells (MSCs) are present in diverse tissues and organs, including bone marrow, umbilical cord, adipose tissue, and placenta. MSCs can expand easily in vitro and have regenerative stem cell properties and potent immunoregulatory activity. They inhibit the functions of dendritic cells, B cells, and T cells, but enhance those of regulatory T cells by producing immunoregulatory molecules such as transforming growth factor-beta, hepatic growth factors, prostaglandin E2, interleukin-10, indolamine 2,3-dioxygenase, nitric oxide, heme oxygenase-1, and human leukocyte antigen-G. These properties make MSCs promising therapeutic candidates for the treatment of autoimmune diseases. Here, we review the preclinical studies of MSCs in animal models for systemic lupus erythematosus, rheumatoid arthritis, Crohn's disease, and experimental autoimmune encephalomyelitis, and summarize the underlying immunoregulatory mechanisms.

Inhibition of Human Pancreatic Tumor Growth by Cytokine-Induced Killer Cells in Nude Mouse Xenograft Model

Pancreatic cancer is the fourth commonest cause of cancer-related deaths in the world. However, no adequate therapy for pancreatic cancer has yet been found. In this study, the antitumor activity of cytokine-induced killer (CIK) cells against the human pancreatic cancer was evaluated in vitro and in vivo. Human peripheral blood mononuclear cells were cultured with IL-2-containing medium in anti-CD3 for 14 days. The resulting populations of CIK cells comprised 94% CD3+, 4% CD3-CD56+, 41% CD3+CD56+, 11% CD4+, and 73% CD8+. This heterogeneous cell population was called cytokine-induced killer (CIK) cells. At an effector-target cell ratio of 100:1, CIK cells destroyed 51% of AsPC-1 human pancreatic cancer cells, as measured by the 51Cr-release assay. In addition, CIK cells at doses of 3 and 10 million cells per mouse inhibited 42% and 70% of AsPC-1 tumor growth in nude mouse xenograft assays, respectively. This study suggests that CIK cells may be used as an adoptive immunotherapy for pancreatic cancer patients.

Dendritic Cell Activation by Glucan Isolated from Umbilicaria Esculenta

BACKGROUND: Lichen-derived glucans have been known to stimulate the functions of immune cells. However, immunostimulatory activity of glucan obtained from edible lichen, Umbilicaria esculenta, has not been reported. Thus we evaluated the phenotype and functional maturation of dendritic cells (DCs) following treatment of extracted glucan (PUE). METHODS: The phenotypic and functional maturation of PUE-treated DCs was assessed by flow cytometric analysis and cytokine production, respectively. PUE-treated DCs was also used for mixed leukocyte reaction to evaluate T cell-priming capacity. Finally we detected the activation of MAPK and NF-kappaB by immunoblot. RESULTS: Phenotypic maturation of DCs was shown by the elevated expressions of CD40, CD80, CD86, and MHC class I/II molecules. Functional activation of DCs was proved by increased cytokine production of IL-12, IL-1beta, TNF-alpha, and IFN-alpha/beta, decreased endocytosis, and enhanced proliferation of allogenic T cells. Polymyxin B, specific inhibitor of lipopolysaccharide (LPS), did not affect PUE activity, which suggested that PUE was free of LPS contamination. As a mechanism of action, PUE increased phosphorylation of ERK, JNK, and p38 MAPKs, and enhanced nuclear translocation of NF-kappaB p50/p65 in DCs. CONCLUSION: These results indicate that PUE induced DC maturation via MAPK and NF-kappaB signaling pathways.