Lupus
 

Systemic Lupus Erythematosus, considered a collection of diseases, is an auto-immune disorder in which the immune system attacks healthy tissues, especially in the joints (especially fingers, wrists, hands, and knees). Patients often develop fatigue, rash, and swollen lymph nodes, but many body parts can be affected. As with other auto-immune conditions, anti-inflammatory medications and immune-suppressants are used commonly for treatment. Sometimes cytotoxic drugs are used for severe cases. Research is also ongoing to evaluate the effects of stem cells on auto-immune conditions.

 

We use a specific SVF deployment protocol that attempts to utilize the immuno-regulatory and anti-inflammatory properties of SVF (rich in mesenchymal stem cells and growth factors) to mitigate the effects of Lupus. SVF is deployed systemically and may require repeat dosing. This is done as an outpatient at the time of SVF harvesting and procurement. The entire cellular surgical procedure takes approximately three hours.

We care about our Lupus patients and take pride in the time we provide to our patients to deploy the best protocols to help our patients achieve their goals. By filling out Confidential Candidate Application, we will answer the questions and concerns you may have about our protocols for Lupus.

 
CANDIDATE APPLICATION
Cell therapy for autoimmune diseases.

Arthritis Res Ther. 2007;9(2):206 Authors: Dazzi F, van Laar JM, Cope A, Tyndall A

Cell therapy, pioneered for the treatment of malignancies in the form of bone marrow transplantation, has subsequently been tested and successfully employed in autoimmune diseases. Autologous haemopoietic stem cell transplantation (HSCT) has become a curative option for conditions with very poor prognosis such as severe forms of scleroderma, multiple sclerosis, and lupus, in which targeted therapies have little or no effect. The refinement of the conditioning regimens has virtually eliminated transplant-related mortality, thus making HSCT a relatively safe choice. Although HSCT remains a nonspecific approach, the knowledge gained in this field has led to the identification of new avenues. In fact, it has become evident that the therapeutic efficacy of HSCT cannot merely be the consequence of a high-dose immuno-suppression, but rather the result of a resetting of the abnormal immune regulation underlying autoimmune conditions. The identification of professional and nonprofessional immunosuppressive cells and their biological properties is generating a huge interest for their clinical exploitation. Regulatory T cells, found abnormal in several autoimmune diseases, have been proposed as central to achieve long-term remissions. Mesenchymal stem cells of bone marrow origin have more recently been shown not only to be able to differentiate into multiple tissues, but also to exert a potent antiproliferative effect that results in the inhibition of immune responses and prolonged survival of haemopoietic stem cells. All of these potential resources clearly need to be investigated at the preclinical level but support a great deal of enthusiasm for cell therapy of autoimmune diseases.

PMID: 17367542 [PubMed – indexed for MEDLINE]

 


Transplantation of Adipose Tissue-Derived Mesenchymal Stem Cells Prevents the Development of Lupus Dermatitis.
 
Stem Cells Dev. 2015 Sep 1;24(17):2041-51. doi: 10.1089/scd.2015.0021. Epub 2015 Jun 17. Choi EW1,2, Shin IS3, Song JW1, Yun TW1, Yang J1,2, Choi KS1,2, Seong JK4.

Abstract
 

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.

 
ReMobilization, harvesting and selection of peripheral blood stem cells in patients with autoimmune diseases undergoing autologous hematopoietic stem cell transplantation.

Bone Marrow Transplant. 2007 Mar;39(6):317-29

Authors: Statkute L, Verda L, Oyama Y, Traynor A, Villa M, Shook T, Clifton R, Jovanovic B, Satkus J, Loh Y, Quigley K, Yaung K, Gonda E, Krosnjar N, Spahovic D, Burt RK

Peripheral blood stem cells (PBSC) were mobilized in 130 patients with autoimmune diseases undergoing autologous hematopoietic stem cell transplantation using cyclophosphamide 2 g/m(2) and either granulocyte colony-stimulating factor (G-CSF) 5 mcg/kg/day (for systemic lupus erythematosus (SLE) and secondary progressive multiple sclerosis, SPMS) or G-CSF 10 mcg/kg/day (for relapsing remitting multiple sclerosis (RRMS), Crohn’s disease (CD), systemic sclerosis (SSc), and other immune-mediated disorders). Mobilization-related mortality was 0.8% (one of 130) secondary to infection. Circulating peripheral blood (PB) CD34(+) cells/microl differed significantly by disease. Collected CD34(+) cells/kg/apheresis and overall collection efficiency was significantly better using Spectra apheresis device compared to the Fenwall CS3000 instrument. Patients with SLE and RRMS achieved the lowest and the highest CD34(+) cell yields, respectively. Ex vivo CD34(+) cell selection employing Isolex 300iv2.5 apparatus was significantly more efficient compared to CEPRATE CS device. Circulating PB CD34(+) cells/microl correlated positively with initial CD34(+) cells/kg/apheresis and enriched product CD34(+) cells/kg. Mean WBC and platelet engraftment (ANC>0.5 x 10(9)/l and platelet count >20 x 10(9)/l) occurred on days 9 and 11, respectively. Infused CD34(+) cell/kg dose showed significant direct correlation with faster white blood cell (WBC) and platelet engraftment. When adjusted for CD34(+) cell/kg dose, patients treated with a myeloablative regimen had significantly slower WBC and platelet recovery compared to non-myeloablative regimens.

PMID: 17277794 [PubMed – indexed for MEDLINE]

 
Haemopoietic stem cell transplantation–an evolving treatment for severe autoimmune and inflammatory diseases in rheumatology, neurology and gastroenterology.

Hematology. 2007 Jun;12(3):179-91 Authors: Kapoor S, Wilson AG, Sharrack B, Lobo A, Akil M, Sun L, Dalley CD, Snowden JA

The concept of haemopoietic stem cell transplantation (HSCT) to treat severe autoimmune diseases has been around for several decades. Advances in the safety of HSCT have made it a clinical reality since 1995. Databases have registered around a thousand patients treated specifically for a wide range of diseases, predominantly multiple sclerosis (MS), systemic sclerosis (SSc), rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Phase I/II prospective and retrospective studies have supported the potential of autologous HSCT as a treatment option in severely affected patients, with profound and prolonged clinical responses in some diseases, although procedures are generally not curative. Allogeneic HSCT appears to offer curative potential, but the potential of high toxicity has limited its use in this context. The exact role of HSCT remains to be defined, particularly in the context of other advances in the treatment of autoimmune disease. Along with other groups, the European Group for Blood and Marrow Transplantation (EBMT) are overseeing several phase III trials in autologous transplantation. Given the risks of the HSCT, eligibility is restricted to patients who have severe, treatment resistant disease, in whom the prognosis is otherwise poor. This review aims to summarise the current published data in this evolving treatment for relatively rare patients with resistant or rapidly progressive disease where treatment options are otherwise limited. This cross-fertilization of knowledge between many specialties may provide increasing therapeutic opportunities in otherwise untreatable diseases. Moreover, destroying and rebuilding immune systems may provide insights into autoimmune diseases.

PMID: 17558693 [PubMed – indexed for MEDLINE]

 
The use of stem cells for the treatment of autoimmune diseases.

Braz J Med Biol Res. 2007 Dec;40(12):1579-97 Authors: Rosa SB, Voltarelli JC, Chies JA, Pranke P

Autoimmune diseases constitute a heterogeneous group of conditions commonly treated with anti-inflammatory, immunosuppressant and immunomodulating drugs, with satisfactory results in most cases. Nevertheless, some patients become resistant to conventional therapy. The use of high doses of drugs in such cases results in the need for bone marrow reconstitution, a situation which has stimulated research into the use of hematopoietic stem cells in autoimmune disease therapy. Stem cell transplantation in such diseases aims to destroy the self-reacting immune cells and produce a new functional immune system, as well as substitute cells for tissue damaged in the course of the disease. Significant results, such as the reestablishment of tolerance and a decrease in the recurrence of autoimmune disease, have been reported following stem cell transplantation in patients with autoimmune disease in Brazil and throughout the world. These results suggest that stem cell transplantation has the potential to become an important therapeutic approach to the treatment of various autoimmune diseases including rheumatoid arthritis, juvenile idiopathic arthritis, systemic lupus erythematosus, multiple sclerosis, systemic sclerosis, Crohn’s disease, autoimmune blood cytopenias, and type I diabetes mellitus.

PMID: 17713674 [PubMed – indexed for MEDLINE]

 
Autologous hematopoietic stem cell transplantation for autoimmune diseases: an observational study on 12 years’ experience from the European Group for Blood and Marrow Transplantation Working Party on Autoimmune Diseases.

Haematologica. 2010 Feb;95(2):284-92 Authors: Farge D, Labopin M, Tyndall A, Fassas A, Mancardi GL, Van Laar J, Ouyang J, Kozak T, Moore J, Kötter I, Chesnel V, Marmont A, Gratwohl A, Saccardi R

BACKGROUND: Autologous hematopoietic stem cell transplantation has been used since 1996 for the treatment of severe autoimmune diseases refractory to approved therapies. We evaluated the long-term outcomes of these transplants and aimed to identify potential prognostic factors.

DESIGN AND METHODS: In this observational study we analyzed all first autologous hematopoietic stem cell transplants for autoimmune diseases reported to the European Group for Blood and Marrow Transplantation (EBMT) registry between 1996-2007. The primary end-points for analysis were overall survival, progression-free survival and transplant-related mortality at 100 days.

RESULTS: Nine hundred patients with autoimmune diseases (64% female; median age, 35 years) who underwent a first autologous hematopoietic stem cell transplant were included. The main diseases were multiple sclerosis (n=345), systemic sclerosis (n=175), systemic lupus erythematosus (n=85), rheumatoid arthritis (n=89), juvenile arthritis (n=65), and hematologic immune cytopenia (n=37). Among all patients, the 5-year survival was 85% and the progression-free survival 43%, although the rates varied widely according to the type of autoimmune disease. By multivariate analysis, the 100-day transplant-related mortality was associated with the transplant centers’ experience (P=0.003) and type of autoimmune disease (P=0.03). No significant influence of transplant technique was identified. Age less than 35 years (P=0.004), transplantation after 2000 (P=0.0015) and diagnosis (P=0.0007) were associated with progression-free survival.

CONCLUSIONS: This largest cohort studied worldwide shows that autologous hematopoietic stem cell transplantation can induce sustained remissions for more than 5 years in patients with severe autoimmune diseases refractory to conventional therapy. The type of autoimmune disease, rather than transplant technique, was the most relevant determinant of outcome. Results improved with time and were associated with the transplant centers’ experience. These data support ongoing and planned phase III trials to evaluate the place of autologous hematopoietic stem cell transplantation in the treatment strategy for severe autoimmune diseases.

PMID: 19773265 [PubMed – indexed for MEDLINE]

 
Technology Insight: hematopoietic stem cell transplantation for systemic rheumatic disease.

Nat Clin Pract Rheumatol. 2008 Apr;4(4):184-91 Authors: Nikolov NP, Pavletic SZ

Hematopoietic stem cells (HSCs) have the capacity for self-renewal and the potential to differentiate into all types of hematopoietic and immune system cells. These features have been successfully used to treat a multitude of hematologic malignancies and nonmalignant diseases such as aplastic anemia, hemoglobinopathies, inborn errors of metabolism and congenital immunodeficiency states. The application of HSC transplantation has been expanded over the past decade to include immune-mediated diseases such as multiple sclerosis, treatment-refractory rheumatoid arthritis, systemic lupus erythematosus and systemic sclerosis. Transplantation of HSCs for the treatment of autoimmune diseases aims to fundamentally correct the dysregulated immune system, which could result in sustained clinical remission or potential cure. The use of this approach is currently restricted to clinical research, as there is no standard conditioning regimen to attain these aims in autoimmune diseases. HSC transplantation is associated with inherent morbidity and mortality, both treatment-related and disease-related, and selecting the correct group of patients with the best risk:benefit ratio is a challenging task.

PMID: 18285764 [PubMed – indexed for MEDLINE]

 
Mesenchymal stem cells and immunomodulation: toward new immunosuppressive strategies for the treatment of autoimmune diseases?

Rev Med Interne. 2009 Mar;30(3):287-99. Epub 2008 Oct 17. Larghero J, Vija L, Lecourt S, Michel L, Verrecchia F, Farge D.

Source

Unité de thérapie cellulaire, Hôpital Saint-Louis, AP-HP, Paris, France.

Abstract

Mesenchymal stem cells (MSC) represent a population of the bone marrow microenvironment, which participates in the regulation of haematopoietic stem cells (HSC) self-renewal and differentiation. MSC are multipotent non-haematopoietic progenitors, which have been explored as a promising treatment in tissue regeneration. Both in vitro and in vivo, the MSC inhibit the T, B, NK and dendritic cell functions. Although MSC immunomodulating properties are not yet completely understood, their low immunogenic potential can be used as a therapeutic tool not only for regenerative medicine, but also for the treatment of graft-versus-host disease (GVHD) after bone marrow transplantation as well as for specific cases of severe refractory autoimmune diseases. Experimental and clinical data gave encouraging results, showing that MSC injection allowed controlling refractory GVHD, restoring bone development in children with osteogenesis imperfecta or improving heart function after myocardial infarction. Phase I-II studies are in progress in various countries to investigate the potential benefit from MSC due to their immunosuppressive properties, as an adjunctive therapy for severe refractory autoimmune disease.

PMID: 18930338 [PubMed – indexed for MEDLINE]

 
Autologous stem cell transplantation for severe autoimmune diseases: a 10-year experience.

Ann N Y Acad Sci. 2007 Sep;1110:455-64 Authors: Gualandi F, Bruno B, Van Lint MT, Luchetti S, Uccelli A, Capello E, Mancardi GL, Bacigalupo A, Marmont A

The first autologous hematopoietic stem cell transplantation in Europe for a patient with severe refractory systemic lupus erythematosus (SLE) was performed in Genoa in 1996. Since then, 32 patients with a wide spectrum of autoimmune diseases (ADs) received autologous transplants, 22 of them with multiple sclerosis (MS). There were no fatal adverse events. All patients had complete or very good partial remissions, but relapses were frequent, especially in SLE, though never as aggressive as pretransplant. The mechanism of action of this intervention remains not completely understood, as briefly discussed here.

PMID: 17911461 [PubMed – indexed for MEDLINE]

 
Multipotent mesenchymal stromal cells for autoimmune diseases: teaching new dogs old tricks.

Tyndall A, Uccelli A.

Source

Department of Rheumatology, University of Basel, University Rheumatology Clinic, Basel, Switzerland. alan.tyndall@fps-basel.ch

Abstract

MSCs, otherwise known as multipotent mesenchymal stromal cells, are being examined for the treatment of autoimmune disease (AD) on the basis of their in vitro antiproliferative properties, efficacy in animal models, apparent low acute toxicity and the early positive anecdotal outcomes in human acute GVHD. Phase I/II clinical trials are underway in Crohn’s disease and multiple sclerosis (MS) and are being planned for systemic lupus erythematosus (SLE), systemic sclerosis (SSc), systemic vasculitis and other AD. Open issues include patient selection, disease stage and activity, MSC source and expansion and long-term safety. Multidisciplinary groups are collaborating to ensure maximal use of available resources to establish the place, if any, of MSC in the treatment of AD.

PMID: 19308035 [PubMed – indexed for MEDLINE]

 
Adult stem cells in the treatment of autoimmune diseases.

Rheumatology (Oxford). 2006 Oct;45(10):1187-93Authors: van Laar JM, Tyndall A

During the past 10 yrs, over 700 patients suffering from severe autoimmune disease (AD) have received an autologous haematopoietic stem cell transplant as treatment of their disorder with durable remission being obtained in around one-third. The most commonly transplanted ADs have been systemic sclerosis (scleroderma), multiple sclerosis, rheumatoid arthritis, juvenile idiopathic arthritis and systemic lupus erythematosus. A fewer number of patients have received an allogeneic transplant. The initially reported overall treatment-related mortality of 7% has since fallen, with no further cases being reported in systemic sclerosis or multiple sclerosis in the past 3 yrs. This is thought to be due to more careful patient selection. The phase I/II data has led to currently running prospective randomised trials in systemic sclerosis, multiple sclerosis and systemic lupus erythematosus in Europe and North America. Immune reconstitution data suggests a ‘resetting’ of autoimmunity in those patients achieving stable remission, rather than simply prolonged immunosuppression. Recent results from in vitro experiments, animal models and early human experience in severe acute graft vs host disease suggest that multipotent mesenchymal stromal cells obtained from the bone marrow and expanded ex vivo, may exert a clinically useful immunomodulatory effect. Such cells are immune privileged and apparently of low toxicity. Further characterization of these cells and consideration of their possible clinical application in AD is underway.

PMID: 16777856 [PubMed – indexed for MEDLINE]

 

 
Hematopoietic stem cell transplantation in autoimmune diseases.

Medicina (B Aires). 2008;68(2):153-63 Authors: Albarracín F, López Meiller MJ, Naswetter G, Longoni H

Transplantation of hematopoietic stem cells, which are capable of self renewal and reconstitution of all types of blood cells, can be a treatment for numerous potential lethal diseases, including leukemias and lymphomas. It may now be applicable for the treatment of severe autoimmune diseases, such as therapy-resistant multiple sclerosis, lupus and systemic sclerosis. Studies in animal models show that the transfer of hematopoietic stem cells can reverse autoimmunity. The outcome of ongoing clinical trials, as well as of studies in patients and animal models, will help to determine the role that stem-cell transplantation can play in the treatment of autoimmune diseases.

PMID: 18499968 [PubMed – indexed for MEDLINE]

 
Immunoregulatory effect of bone marrow mesenchymal stem cells on regulatory T cells in patients with systemic lupus erythematosis

Zhonghua Nei Ke Za Zhi. 2007 Dec;46(12):1018-2

 Authors: Sun Y, Zhang FS, Zhang ZY

OBJECTIVE: To study the in vitro modulation of autogeneic and allogenic regulatory T lymphocytes proliferation by bone marrow mesenchymal stem cells (MSCs) in patients with systemic lupus erythematosis (SLE). METHODS: Human MSCs were separated with Percoll (1.073 g/ml) from bone marrow of patients with SLE or healthy subjects. The purity of MSCs was identified with the phenotypes by fluorescence active cell sorter (FACS). The subset regulatory T cells in the peripheral blood of patients with SLE were isolated with magnetic activated cell sorting (MACS) CD4 and CD25 microbeads. Lymphocytes or CD4+ CD25+ T cells isolated from the peripheral blood of SLE patients were cocultured either with autologous MSCs or MSCs from healty donors. The proliferation activities of lymphocytes and CD4+ CD25+ T cells were investigated with methyl thiazolyl tetrazolium( MTr) test. The level of IL-10 and transforming growth factor beta (TGFbeta) was determined with enzyme-linked immunosorbent assay (ELISA). RESULTS: The lymphocyte activity in SLE was suppressed by autogeneic and allogeneic MSCs and the inhibition rate was 56.32% and 65.46%, respectively. A stronger immunosuppressive effect of allogeneic MSCs was detected. MSCs were capable of increasing the proportion of allogeneic and autogeneic regulatory T cells in a dose dependent fashion. MSCs stimulated CD4+ CD25+ T cells to produce IL-10 and TGFbeta. CONCLUSION: MSCs can suppress lymphocyte proliferation and increase CD4+ CD25+ T cells. MSCs might play important roles in immunosuppressant lymphocyte proliferation and be important to cooperate with autogeneic hematopoietic stem cells in transplantation.

PMID: 18478921 [PubMed – indexed for MEDLINE]


Allogeneic adipose-derived stem cells suppress Th17 lymphocytes in patients with active lupus in vitro.
 
Acta Biochim Biophys Sin (Shanghai). 2011 Oct;43(10):805-12. doi: 10.1093/abbs/gmr077. Epub 2011 Sep 7. Lai K1, Zeng K, Zeng F, Wei J, Tan G.

Abstract
 

Interleukin-17 (IL-17)-producing CD4(+) T cells (Th17 cells) have been proven to play a critical role in the pathogenesis of systemic lupus erythematosus (SLE). To shed light on the mechanism of immunoregulation of adipose-derived stem cells (ADSCs), we investigated the effects of allogeneic ADSCs on the Th17 lymphocytes of patients with active SLE by co-culturing ADSCs and peripheral blood mononuclear cells of these patients in vitro. The results indicated that ADSCs from passage 3 (P3) down-regulated the proportion of Th17 cells and their abilities to produce IL-17, whereas ADSCs from passage 8 (P8) had contrasting effect. The results also showed cell-cell contact played a role in P3 down-regulation. Blocking the functional pathway of IL-23 (both its ligand and its receptor) also contributed to this suppression. These results suggested that immunomodulation of ADSCs may be achieved by partially suppressing the number and capability of Th17 lymphocytes, indicating that ADSCs could be employed as therapeutic tools for the autoimmune diseases.

 

Transplantation of Adipose Tissue-Derived Mesenchymal Stem Cells Prevents the Development of Lupus Dermatitis.
 
Stem Cells Dev. 2015 Sep 1;24(17):2041-51. doi: 10.1089/scd.2015.0021. Epub 2015 Jun 17.

Choi EW1,2, Shin IS3, Song JW1, Yun TW1, Yang J1,2, Choi KS1,2, Seong JK4.

Abstract
 

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.

 
 
RESOURCES

Therapeutic Effects of Umbilical Cord Blood-Derived Mesenchymal Stem Cell Transplantation in Experimental Lupus Nephritis.

Cell Transplant. 2010 Aug 18; Authors: Chang JW, Hung SP, Wu HH, Wu WM, Yang AH, Tsai HL, Yang LY, Lee OK

Msenchymal stem cells (MSCs) have been shown to possess immuno-modulatory properties. Systemic lupus erythematosus is an autoimmune disease which results in nephritis and subsequent destruction of renal microstructure. We investigated whether human umbilical cord blood-derived MSCs (uMSCs) transplantation is useful in alleviating lupus nephritis in a murine model. It was found that uMSCs transplantation significantly delayed the development of proteinuria, decreased anti-dsDNA, alleviated renal injury, and prolonged the life span. There was a trend of decreasing T-helper (Th) 1 cytokines (IFN-Upsilon, IL-2) and pro-inflammatory cytokines (TNF-alpha, IL-6, IL-12) and increasing Th2 cytokines (IL-4, IL-10). The in vitro co-culture experiments showed that uMSCs only inhibited lymphocytes and splenocytes proliferation but not mesangial cells. Long-term engraftment of uMSCs in the kidney was not observed either. Together, these findings indicated that uMSCs were effective in decreasing renal inflammation and alleviating experimental lupus nephritis by inhibiting lymphocytes, inducing polarization of Th2 cytokines and inhibition of pro-inflammatory cytokines production rather than direct engraftment and differentiating into renal tissue. Therapeutic effects demonstrated in this pre-clinical study support further exploration of the possibility to use uMSCs from mismatched donors in lupus nephritis treatment.

PMID: 20719085 [PubMed – as supplied by publisher]

 
Autoimmune disease: is it a disorder of the microenvironment?

Immunol Res. 2008;41(1):79-86 Authors: El-Badri NS, Hakki A, Ferrari A, Shamekh R, Good RA

Systemic lupus erythematosus (SLE) is a common systemic autoimmune disease that involves several vital organs including the cardiovascular system, joints, and kidneys. The pathology is characterized by accumulation of autoreactive lymphocytes that attack the patients’ own tissues, secretion of autoantibodies and deposition of immune complexes in vital organs. Chronic widespread inflammation is the hallmark of SLE and the target of current therapy. According to recent theories, intonating immune circuits of inflammatory cytokines and immune cells constitute highly specialized targets for SLE therapy, which nonetheless consists for the most part of anti-inflammatory medications and cytotoxic drugs. For advanced autoimmune disorders, cell therapy aiming at introducing “healthy” stem cells has been promising, keeping in mind that in its current state, stem cell therapy is reserved for the most advanced diseases refractory to traditional therapy. Ongoing studies in our laboratories examined the role of the bone marrow microenvironment, in particular, mesenchymal stem cells (MSCs) in the etiopathogenesis of SLE. Specifically, we are testing the hypothesis that, in human SLE mouse model, marrow MSCs are defective structurally and functionally. Preliminary data indicate that structural and functional defects in MSC population from an autoimmune mouse model for human SLE may contribute to this pathology and consequently present a target for cell therapy.

PMID: 18506645 [PubMed – indexed for MEDLINE]

 
Mesenchymal stem cell transplantation reverses multiorgan dysfunction in systemic lupus erythematosus mice and humans.

Stem Cells. 2009 Jun;27(6):1421-32. Sun L, Akiyama K, Zhang H, Yamaza T, Hou Y, Zhao S, Xu T, Le A, Shi S.

Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.

Abstract

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease that, despite the advances in immunosuppressive medical therapies, remains potentially fatal in some patients, especially in treatment-refractory patients. Here, we reported that impairment of bone marrow mesenchymal stem cells (BMMSCs) and their associated osteoblastic niche deficiency contribute in part to the pathogenesis of SLE-like disease in MRL/lpr mice. Interestingly, allogenic BMMSC transplantation (MSCT) is capable of reconstructing the bone marrow osteoblastic niche and more effectively reverses multiorgan dysfunction when compared with medical immunosuppression with cyclophosphamide (CTX). At the cellular level, MSCT, not CTX treatment, was capable to induce osteoblastic niche reconstruction, possibly contributing to the recovery of regulatory T-cells and reestablishment of the immune homeostasis. On the basis of the promising clinical outcomes in SLE mice, we treated four CTX/glucocorticoid treatment-refractory SLE patients using allogenic MSCT and showed a stable 12-18 months disease remission in all treated patients. The patients benefited an amelioration of disease activity, improvement in serologic markers and renal function. These early evidences suggest that allogenic MSCT may be a feasible and safe salvage therapy in refractory SLE patients.

PMID: 19489103 [PubMed – indexed for MEDLINE] PMCID: PMC2704254

 
Novel therapeutic approaches in systemic lupus erythematosus.

Front Biosci (Schol Ed). 2010 Jan 1;2:221-8. Kiss E, Szodoray P.

National Institute of Rheumatology and Physiotherapy, Budapest, Hungary.

Abstract

Systemic lupus erythematosus is a prototypical systemic autoimmune disease, affecting multiple organs and organ-systems, leading to a wide variety of symptoms, serological and clinical features. The pathogenesis of the disease encompasses a complex interplay among various immune-competent cells and inflammatory mediators, which gives ground to target numerous potentially harmful players in this system. The aim of the present review was to depict certain aspects on the pathogenesis of SLE and to highlight pathways that can be promising targets of novel therapeutic approaches. T-cell, B-cell targeting, modification of co-stimulatory pathways, anti-cytokine therapy, soluble mediators, as well as autologous stem cell transplantation have been addressed. Finally, we described potential side effects of these biologics.

PMID: 20036942 [PubMed – indexed for MEDLINE]

 
Novel therapeutic possibilities in systemic lupus erythematosus.

Orv Hetil. 2010 May 2;151(18):735-40. Bazsó A, Poór G, Gergely P, Kiss E.

Országos Reumatológiai és Fizioterápiás Intézet, Budapest.

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disorder involving different organs and organ systems with consequent characteristic clinical and serologic symptoms. Despite of the improvement in lupus survival, approximately 10-20% of patients do not respond to traditional immune suppressive therapies. Relapses are more frequent; e.g. after cyclophosphamide therapy diffuse proliferative nephritis flares in 1/3 of patients. Different immune competent cells and inflammatory mediators participate in the pathogenesis of SLE involving both the adaptive and innate immunity. Several pathogenic elements and mechanisms may serve as therapeutic targets, consequently. Authors summarize novel therapeutic possibilities and their mechanisms regarding the pathogenesis of SLE. Immune modulation of B and T cells, co-stimulatory pathways, cytokine network, soluble mediators and autologous hemopoietic stem cell transplantation are discussed.

PMID: 20410000 [PubMed – indexed for MEDLINE]

 
Allogenic mesenchymal stem cells transplantation in refractory systemic lupus erythematosus: a pilot clinical study.

Ann Rheum Dis. 2010 Aug;69(8):1423-9. Liang J, Zhang H, Hua B, Wang H, Lu L, Shi S, Hou Y, Zeng X, Gilkeson GS, Sun L

Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.

Erratum in

Ann Rheum Dis. 2011 Jan;70(1):237.

Abstract

OBJECTIVE: To determine the safety and efficacy of allogeneic mesenchymal stem cell transplantation (MSCT) in refractory systemic lupus erythematosus (SLE).

METHODS: A total of 15 patients with persistently active SLE underwent MSCT. Outcome was evaluated by changes in the SLE disease activity index (SLEDAI), serological features (anti-nuclear antibodies and anti-double-stranded DNA (anti-dsDNA)), renal function and percentage of peripheral blood regulatory T cells.

RESULTS: From 11 March 2007 to 4 November 2008, 15 patients with persistently active SLE were enrolled and underwent MSCT. The mean follow-up period was 17.2+/-9.5 months. A total of 13 patients have been followed for more than 12 months. All patients clinically improved following treatment with mesenchymal stem cells with a marked decrease in the SLEDAI score and 24 h proteinuria. At 12-month follow-up, SLEDAI scores decreased from 12.2+/-3.3 to 3.2+/-2.8 and proteinuria decreased from 2505.0+/-1323.9 to 858.0+/-800.7 mg/24 h (all p<0.05, by paired t test, n=12). At 1-year follow-up in 13 patients, 2 had a relapse of proteinuria, while the other 11 continue to have decreased disease activity on minimal treatment. Anti-dsDNA levels decreased. Improvement in glomerular filtration rate was noted in two patients in which formal testing was performed. Non-renal-related manifestations also improved significantly. No serious adverse events were reported.

CONCLUSION: Allogeneic MSCT in patients with refractory lupus resulted in amelioration of disease activity, improvement in serological markers and stabilisation of renal function. MSCT appears beneficial in treatment of patients with SLE refractory to conventional treatment options.

Comment in

Mesenchymal stem cells in the treatment of autoimmune diseases. [Ann Rheum Dis. 2010]

 
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