카테고리: 면역계

Transplantation of CTLA4Ig gene-transduced adipose tissue-derived mesenchymal stem cells reduces inflammatory immune response and improves Th1/Th2 balance in experimental autoimmune thyroiditis.

요약 : 
Background: Autoimmune thyroiditis is one of common organ-specific autoimmune disease. The aim of this study was to observe the effect of adipose tissue derived mesenchymal stem cells (ATMSC) and CTLA4Ig genetransduced ATMSC on autoimmune thyroiditis. Methods Experimental autoimmune thyroiditis was induced by immunization with thyroglobulin. Animals were divided into three groups: (i) a half million of human ATMSC, (ii) a half million of murine CLTA4Ig gene-transduced human ATMSC (CTLA4Ig-MSC), or (iii) normal saline (as control), which were administered intravenously four times within a 3-week period. Blood and tissue samples were collected 1 week after the last cell transplantation.

Characteristics of mouse adipose tissue-derived stem cells and therapeutic comparison between syngeneic and allogeneic adipose tissue-derived stem cell transplantation in experimental autoimmune thyroiditis

요약 : 
Previously, we found that the intravenous administration of human adipose tissue-derived mesenchymal stem cells was a promising therapeutic option for autoimmune thyroiditis even when the cells were transplanted into a xenogeneic model without an immunosuppressant. Therefore, we explored the comparison between the therapeutic effects of syngeneic and allogeneic adipose tissue-derived stem cells on an experimental autoimmune thyroiditis mouse model. Experimental autoimmune thyroiditis was induced in C57BL/6 mice by immunization with porcine thyroglobulin. Adipose tissue-derived stem cells derived from C57BL/6 mice (syngeneic)
or BALB/c mice (allogeneic) or saline as a vehicle control were administered intravenously four times weekly. Blood and tissue samples were collected 1 week after the last transplantation. Adipose tissue-derived stem cells from mice were able to differentiate into multiple lineages in vitro; however, mouse adipose tissuederived stem cells did not have immunophenotypes identical to those from humans. Syngeneic and allogeneic administrations of adipose tissue-derived stem cells reduced thyroglobulin autoantibodies and the inflammatory immune response, protected against lymphocyte infiltration into the thyroid, and restored the Th1/Th2 balance without any adverse effects. However, different humoral immune responses were observed for infused cells from different stem cell sources. The strongest humoral immune response was induced by xenogeneic transplantation, followed by allogeneic and syngeneic administration, in that order. The stem cells were mostly found in the spleen, not the thyroid. This migration might be because the stem cells primarily function in systemic immune modulation, due to being given prior to disease induction. In this study, we confirmed that there were equal effects of adipose tissue-derived stem cells in treating autoimmune thyroiditis between syngeneic and allogeneic transplantations

Stem cell treatment for patients with autoimmune disease by systemic infusion of culture-expanded autologous adipose tissue derived mesenchymal stem cells.

요약 : 
Prolonged life expectancy, life style and environmental changes have caused a changing disease pattern in developed countries towards an increase of degenerative and autoimmune diseases. Stem cells have become a promising tool for their treatment by promoting tissue repair and protection from immune-attack associated damage. Patient-derived autologous stem cells present a safe option for this treatment since these will not induce immune rejection and thus multiple treatments are possible without any risk for allogenic sensitization, which may arise from allogenic stem cell transplantations. Here we report the outcome of treatments with culture expanded human adipose-derived mesenchymal stem cells (hAdMSCs) of 10 patients with autoimmune associated tissue damage and exhausted therapeutic options, including autoimmune hearing loss, multiple sclerosis, polymyotitis, atopic dermatitis and rheumatoid arthritis. For treatment, we developed a standardized culture-expansion protocol for hAdMSCs from minimal amounts of fat tissue, providing sufficient number of cells for repetitive injections. High expansion efficiencies were routinely achieved from autoimmune patients and from elderly donors without measurable loss in safety profile, genetic stability, vitality and differentiation potency, migration and homing characteristics. Although the conclusions that can be drawn from the compassionate use treatments in terms of therapeutic efficacy are only preliminary, the data provide convincing evidence for safety and therapeutic properties of systemically administered AdMSC in human patients with no other treatment options. The authors believe that exvivo-expanded autologous AdMSCs provide a promising alternative for treating autoimmune diseases. Further clinical studies are needed that take into account the results obtained from case studies as those presented here

Reversal of serologic, immunologic, and histologic dysfunction in mice with systemic lupus erythematosus by long-term serial adipose tissue-derived mesenchymal stem cell transplantation.

요약 : 
Objective. To investigate the efficacy of human adipose tissue–derived mesenchymal stem cell (ADMSC) transplantation in systemic lupus erythematosus (SLE) and to determine the optimal transplantation
window for stem cells either before or after disease onset.
Methods. (NZB NZW)F1 mice with SLE were administered human AD-MSCs (5 105) intravenously every 2 weeks from age 6 weeks until age 60 weeks, while the control group received saline vehicle on the same schedule. Another experiment was carried out with a different initiation time point for serial transplantation (age 6 weeks or age 32 weeks).
Results. Long-term serial administration (total of 28 times) of human AD-MSCs ameliorated SLE without any adverse effects. Compared with the control group, the human AD-MSC–treated group had a significantly
higher survival rate with improvement of histologic and serologic abnormalities and immunologic function, and also had a decreased incidence of proteinuria. Anti–double-stranded DNA antibodies and blood urea nitrogen levels decreased significantly with transplantation of human AD-MSCs, and serum levels of granulocyte–macrophage colony-stimulating factor, interleukin-4 (IL-4), and IL-10 increased significantly. A significant
increase in the proportion of CD4 FoxP3 cells and a marked restoration of capacity for cytokine production were observed in spleens from the human AD-MSC–treated group. In the second experiment, an early stage
treatment group showed better results (higher survival rates and lower incidence of proteinuria) than an advanced stage treatment group.
Conclusion. Serial human AD-MSC transplantation had beneficial effects in the treatment of SLE, without adverse effects. Transplantation of human ADMSCs before disease onset was preferable for amelioration of SLE and restoration of immune homeostasis.

Transplantation of Adipose Tissue-Derived Mesenchymal Stem Cells Prevents the Development of Lupus Dermatitis

요약 : 
MRL/lpr mice spontaneously develop high titers of anti-dsDNA antibodies and symptoms such as glomerular nephritis and organ weight gain. They also develop spontaneous skin inflammation similar to the cutaneous
lesions common in human lupus erythematosus. This study aimed to compare the effects of long-term serial administration of human adipose tissue-derived mesenchymal stem cells (ASCs), CTLA4Ig-overexpressing
ASCs, and cyclophosphamide treatment in MRL/lpr mice. MRL/lpr mice were divided into saline (C), cyclophosphamide (Y), ASC early (E), ASC late (L), and CTLA4Ig-overexpressing ASC (CT) treatment groups.
Background-matched control MRL/MPJ mice treated with saline (N) were also compared. The treatment period was 5–23 weeks, except for the L group (15–23 weeks). Blood and tissue samples were collected when the mice were 24 weeks old. Organ weight, anti-dsDNA antibodies, urine protein, skin and kidney histologic abnormalities, and trabecular bone volume were evaluated. The Y group showed the greatest decrease in anti-dsDNA antibodies, organ weight, degree of kidney inflammation and glomerular infiltration of C3, and incidence rate of severe proteinuria; the E, L, and CT treatment groups showed better results than the C group. ASC transplantation reduced anti-dsDNA antibody levels significantly. Mice treated with ASCs or CTLA4Ig-ASCs starting from the early disease stage did not show dermatitis upon gross examination; they demonstrated significant improvement in hyperkeratosis, acanthosis, and inflammatory cell infiltration scores in histopathology. Micro-CT analysis revealed that cyclophosphamide treatment significantly decreased bone volume and increased bone spacing in the trabecular bone. Thus, we found that ASC and CTLA4-ASC treatments prevent lupus dermatitis development in MRL/lpr mice without adverse effects

Reduction of Liver Fibrosis by Xenogeneic Human Umbilical Cord Blood and Adipose Tissue-derived Multipotent Stem Cells without Treatment of an Immunosuppressant

요약 : 
Therapy using stem cells for the liver fibrosis is a prospective alternative to overcome the insufficiency of transplantable liver donor. Here, we demonstrated xenogeneic human cell therapy for the treatment of rat liver
fibrosis without the use of an immunosuppressant. Liver fibrosis was induced by dimethylnitrosamine for 5 weeks in six-week-old male Sprague-Dawley rats. Human umbilical cord blood- and adipose tissue-derived multipotent stem cells were injected intravenously by the tail vein after one week. Blood samples were collected and liver samples were stained with Masson’s trichrome in order to evaluate the amount of fibrosis. After the cell injection, the level of total protein, albumin, alanine transaminase and aspartic acid transaminase was recovered to the similar level of the normal rats. The liver weight per body weight increased after the cell injection. Collagen fiber, near the portal triad and marginal region, was reduced, significantly. Taken together, it is suggested that xenotransplantation of multipotent stem cells might be a candidate for the treatment of liver fibrosis without the use of an immunosuppresant

The therapeutic efficacy of human adipose tissue-derived mesenchymal stem cells on experimental autoimmune hearing loss in mice.

요약 : 
Autoimmune inner ear disease is characterized by progressive, bilateral although asymmetric, sensorineural hearing loss. Patients with autoimmune inner ear disease had higher frequencies of interferon-c-producing
T cells than did control subjects tested. Human adipose-derived mesenchymal stem cells (hASCs) were recently found to suppress effector T cells and inflammatory responses and therefore have beneficial effects in various autoimmune diseases. The aim of this study was to examine the immunosuppressive activity of hASCs on autoreactive T cells from the experimental autoimmune hearing loss (EAHL) murine model. Female BALB/c mice underwent b-tubulin immunization to develop EAHL; mice with EAHL were given hASCs or PBS intraperitoneally once a week for 6 consecutive weeks. Auditory brainstem responses were examined over time. The T helper type 1 (Th1)/Th17-mediated autoreactive responses were examined by determining the proliferative response and cytokine profile of splenocytes stimulated with b-tubulin. The frequency of regulatory T (Treg) cells and their suppressive capacity on autoreactive T cells were also determined. Systemic infusion of hASCs significantly improved hearing function and protected hair cells in established EAHL. The hASCs decreased the proliferation of antigen-specific Th1/Th17 cells and induced the production of anti-inflammatory cytokine interleukin-10 in splenocytes.
They also induced the generation of antigen-specific CD4+ CD25+ Foxp3+ Treg cells with the capacity to suppress autoantigen-specific T-cell responses. The experiment demonstrated that hASCs are one of the important regulators of immune tolerance with the capacity to suppress effector T cells and to induce the generation of antigen-specific Treg cells.

Immunomodulatory effects of human amniotic membrane-derived mesenchymal stem cells

요약 : 
Human amniotic membrane-derived mesenchymal stem cells (hAM-MSCs) are capable of differentiating into several lineages and possess immunomodulatory properties. In this study, we investigated the soluble factor-mediated immunomodulatory effects of hAM-MSCs. Mitogen-induced peripheral blood mononuclear cell (PBMC) proliferation was suppressed by hAM-MSCs in a dose-dependent manner as well as hAM-MSC culture supernatant. Moreover, interferon-gamma and interleukin (IL)-17 production significantly decreased from PBMC, whereas IL-10 from PBMCs and transforming growth factor beta (TGF-β) production from hAM-MSCs significantly increased in co-cultures of hAM-MSCs and PBMCs. Production of several MSC factors, including hepatocyte growth factor (HGF), TGF-β, prostaglandin E2 (PGE2), and indoleamine 2, 3 dioxygenase (IDO), increased significantly in hAM-MSCs co-cultured with PBMCs. These results indicate that the immunomodulatory effects of hAM-MSCs may be associated with soluble factors (TGF-β, HGF, PGE2, and IDO), suggesting that hAM-MSCs may have potential clinical use in regenerative medicine

Evaluation of the potential use of adipose-derived mesenchymal stromal cells in the treatment of canine atopic dermatitis: a pilot study.

요약 : 
Human amniotic membrane-derived mesenchymal stem cells (hAM-MSCs) are capable of differentiating into several lineages and possess immunomodulatory properties. In this study, we investigated the soluble factor-mediated immunomodulatory effects of hAM-MSCs. Mitogen-induced peripheral blood mononuclear cell (PBMC) proliferation was suppressed by hAM-MSCs in a dose-dependent manner as well as hAM-MSC culture supernatant. Moreover, interferon-gamma and interleukin (IL)-17 production significantly decreased from PBMC, whereas IL-10 from PBMCs and transforming growth factor beta (TGF-β) production from hAM-MSCs significantly increased in co-cultures of hAM-MSCs and PBMCs. Production of several MSC factors, including hepatocyte growth factor (HGF), TGF-β, prostaglandin E2 (PGE2), and indoleamine 2, 3 dioxygenase (IDO), increased significantly in hAM-MSCs co-cultured with PBMCs. These results indicate that the immunomodulatory effects of hAM-MSCs may be associated with soluble factors (TGF-β, HGF, PGE2, and IDO), suggesting that hAM-MSCs may have potential clinical use in regenerative medicine

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