Mesenchymal Stem Cells in Immune-Mediated Bone Marrow Failure Syndromes

Increasing interest on the field of autoimmune diseases has unveiled a plethora of genetic factors that predispose to these diseases. However, in immune-mediated bone marrow failure syndromes, such as acquired aplastic anemia and chronic idiopathic neutropenia, in which the pathophysiology results from a myelosuppressive bone marrow microenvironment mainly due to the presence of activated T lymphocytes, leading to the accelerated apoptotic death of the hematopoietic stem and progenitor cells, such genetic associations have been very limited. Various alleles and haplotypes of human leucocyte antigen (HLA) molecules have been implicated in the predisposition of developing the above diseases, as well as polymorphisms of inhibitory cytokines such as interferon-γ, tumor necrosis factor-α, and transforming growth factor-β1 along with polymorphisms on molecules of the immune system including the T-bet transcription factor and signal transducers and activators of transcription. In some cases, specific polymorphisms have been implicated in the outcome of treatment on those patients.

Download Full-text

Bone Marrow-Derived Mesenchymal Stem Cells Attenuate Immune-Mediated Liver Injury and Compromise Virus Control During Acute Hepatitis B Virus Infection in Mice

Stem Cells and Development ◽

10.1089/scd.2016.0348 ◽

2017 ◽

Vol 26 (11) ◽

pp. 818-827 ◽

Cited By ~ 5

Author(s):

Mengmeng Qu ◽

Xu Yuan ◽

Dan Liu ◽

Yuhong Ma ◽

Jun Zhu ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Hepatitis B Virus ◽

Liver Injury ◽

Virus Infection ◽

Hepatitis B Virus Infection ◽

Immune Mediated ◽

B Virus ◽

Acute Hepatitis B

Download Full-text

ULBP and MICA/B as Novel Indicators for Both Diagnosis of Immune-Mediated Marrow Injury and Favorable Response to Immunosuppressive Therapy in Bone Marrow Failure Syndromes.

Blood ◽

10.1182/blood.v108.11.990.990 ◽

2006 ◽

Vol 108 (11) ◽

pp. 990-990

Author(s):

Nobuyoshi Hanaoka ◽

Tatsuya Kawaguchi ◽

Kentaro Horikawa ◽

Shoichi Nagakura ◽

Yasuchika Tsuzuki ◽

...

Keyword(s):

Bone Marrow ◽

Targeted Therapy ◽

Immunosuppressive Therapy ◽

Close Association ◽

Bone Marrow Failure ◽

Γδ T Cells ◽

Nkg2d Ligands ◽

Bone Marrow Failure Syndromes ◽

Immune Mediated ◽

Marrow Cells

Abstract Bone marrow failure syndromes (BFS) including aplastic anemia (AA), myelodysplastic syndromes (MDS), and paroxysmal nocturnal hemoglobinuria (PNH) are considered to harbor immune-mediated marrow injury. Indeed, immunosuppressive therapy (IST) with antithymocyte globulin and cyclosporine ameliorates the hematopoiesis in BFS patients, despite its limit: infrequent relapse of marrow failure after IST, resistance of some patients to IST, and untoward effects like infection. To overcome the difficulties, molecular targeted therapy is alternative. However, neither incitement of marrow injury nor target molecules on marrow cells recognized by cytotoxic lymphocytes has been identified. We have currently suggested that NKG2D ligands such as ULBP and MICA/B serve as triggers for immune-mediated marrow injury in PNH (Hanaoka, Blood2006;107:1184). ULBP and MICA/B are stress-inducible membrane proteins that appear in infection and transformation. The ligands share NKG2D receptor on lymphocytes such as NK, CD8+ T, and γδ T cells and promote activation of the lymphocytes. Cells expressing the ligands are then deadly injured by NKG2D+ cells (Groh, PNAS USA 1996; Cosman, Immunity 2001). In this background, we attempted to confirm the clinical significance of the expression of NKG2D ligands in BFS. The ligands were detected by flow cytometry on the granulocytes and marrow cells in 47 (53%) of 89 patients with BFS: 28 (56%) of 50 patients with AA; 11 (65%) of 17 patients with PNH; 8 (36%) of 22 patients with MDS; and none of 17 healthy individuals. The membrane expression of the ligands was supported by their increase in plasma. It is then conceivable that blood cells were exposed to a certain stress to induce NKG2D ligands in the patients, leading to NKG2D-mediated marrow injury. There was a close association of the expression of NKG2D ligands with both progression of marrow failure and favorable response to IST. Thus, we propose that the NKG2D ligands not only are feasible predictors for both immune-mediated marrow injury and IST effects, but also serve for potential targeted therapy in BFS.

Download Full-text

Decreased MHC-II Expression and Immune Dysfunction by Mesenchymal Stem Cells in the Bone Marrow of Patients with Myeloproliferative Disorders.

Blood ◽

10.1182/blood.v110.11.4647.4647 ◽

2007 ◽

Vol 110 (11) ◽

pp. 4647-4647

Author(s):

Marianne D. Castillo ◽

Pranela Rameshwar

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Hematological Malignancy ◽

Flow Cytometric Analysis ◽

Myeloproliferative Disorders ◽

Bone Marrow Biopsies ◽

Hematological Disorders ◽

Mhc Ii ◽

Immune Mediated

Abstract The etiology of hematological disorders has been studied at the cellular and molecular levels. These studies have led to an understanding of the effects by the bone marrow microenvironment on the pathophysiology of myeloproliferative disorders. The overarching hypothesis states that resident bone marrow Mesenchymal Stem Cells (MSCs) are important in the development of myeloproliferative disorders and are also involved in the development of fibrosis. The specific hypothesis is that MHC-II expression is decreased in patients MSCs. This makes them unable to act as antigen presenting cells and to suppress immune mediated mechanisms that lead to the development of some myeloproliferative disorders. MSCs were expanded from bone marrow aspirates of patients with AML (n=10), CML (n=10), and MDS (n=10). Flow cytometric analysis showed decreased MHC-II expression in MSCs from all patients as compared to MSCs from patients without hematological malignancy. The flow cytometry results were verified in functional studies using the MSCs as stimulators in a one way mixed lymphocyte reaction. Compared to MSCs from non-hematological malignancy patients, MSCs from study subjects showed reduced ability to elicit allogeneic responses. Retrospective analyses of bone marrow biopsies using immunohistochemistry showed an increase in the amount of MSCs in myelofibrosis patients, compared to patients without evidence of fibrosis, alluding to their role in the development of this condition. These results suggest that MSCs may be dysfunctional in patients with hematological disorders. Variations in the immune properties and the increased amount of MSCs in these patients open an avenue for a lingering question on the etiology of the development of some hematological disorders. Do dysfunctions of MSCs precede myeloproliferative disorders and leukemia or does the opposite occur? In summary, we provide insight into the immune-mediated mechanisms related to the pathophysiology of these disorders, which may have clinical implications for future therapies of bone marrow related disease.

Download Full-text

CD106 is a novel mediator of bone marrow mesenchymal stem cells via NF-κB in the bone marrow failure of acquired aplastic anemia

Stem Cell Research & Therapy ◽

10.1186/s13287-017-0620-4 ◽

2017 ◽

Vol 8 (1) ◽

Cited By ~ 10

Author(s):

Shihong Lu ◽

Meili Ge ◽

Yizhou Zheng ◽

Jianping Li ◽

Xiaoming Feng ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Aplastic Anemia ◽

Bone Marrow Failure ◽

Marrow Mesenchymal Stem Cells

Download Full-text

Immunosuppressive Treatment of Acquired Aplastic Anemia and Immune-Mediated Bone Marrow Failure Syndromes

International Journal of Hematology ◽

10.1007/bf02982017 ◽

2002 ◽

Vol 75 (2) ◽

pp. 129-140 ◽

Cited By ~ 13

Author(s):

Neal S. Young

Keyword(s):

Bone Marrow ◽

Aplastic Anemia ◽

Bone Marrow Failure ◽

Immunosuppressive Treatment ◽

Bone Marrow Failure Syndromes ◽

Immune Mediated

Download Full-text

Tumor Necrosis Factor-Alpha and Interleukin-6 Promoter Gene Polymorphisms in Acquired Bone Marrow Failure Syndromes.

Blood ◽

10.1182/blood.v104.11.3707.3707 ◽

2004 ◽

Vol 104 (11) ◽

pp. 3707-3707 ◽

Cited By ~ 2

Author(s):

Vinod K. Gidvani ◽

Shakti H. Ramkissoon ◽

Elaine W. Wong ◽

Lori Mainwaring ◽

Elaine M. Sloand ◽

...

Keyword(s):

Bone Marrow ◽

Bone Marrow Failure ◽

Cytokine Gene ◽

Nucleotide Polymorphism ◽

Single Nucleotide ◽

Bone Marrow Failure Syndromes ◽

Immune Mediated ◽

Tnf Α ◽

Historical Controls ◽

Pro Inflammatory Cytokines

Abstract Some acquired aplastic anemia (AA) results from immune mediated destruction of the hematopoetic stem cells. Immunosuppressive therapy is successful in majority of AA patients and substantial laboratory data are consistent with an immune pathophysiology. Substantial research has implicated differences in cytokine gene expression profiles and polymorphisms in the genes controlling cytokine expression in other autoimmune diseases such as lupus erythematosus and rheumatoid arthritis. Interlukin-6 (IL-6) and tumor necrosis alpha (TNF-α) are two potent pro-inflammatory cytokines that have implicated in a variety of immune-mediated conditions. TNF-α results in Fas expression and apoptosis of in progenitor cells and the TNF-alpha −308 allele was significantly associated with SLE in Caucasians. Levels both IL-6 and TNF-α have been reported elevated in AA patients. In the promoter region of the IL-6 gene, at position −174, exists a single nucleotide polymorphism (G/C) in close proximity to a glucocorticoid-responsive element; patients homozygous for the G allele have circulating IL-6 concentrations close to twice as high as those homozygous for the C allele. The TNF-α gene, located in the class III region of the major histocompatibility complex (MHC), has a polymorphism at position −308, TNF2, where the presence of adenine instead of guanine is associated with higher cytokine production. In our study, we characterized the IL-6/−174 and the TNF-α/−308 polymorphisms in patients with acquired bone marrow failure syndromes to assess if the higher production genotypes were more prevalent that in established controls. We identified seventy-three patients (age range 3–84) treated at our institution for AA. Following an established protocol for the identification of single nucleotide polymorphisms, genomic DNA was amplified with primers designed for the promoter regions of the IL-6 and TNF-α genes where intentional mismatches were inserted at 1–3 nucleotide positions to incorporate a restriction site for endonucleases. The amplicons were digested with four restriction endonucleases (BlsI, BsaBI, EcoNI, RsaI) then analyzed by electrophoresis in 3% agarose gels. The resulting fragments allowed for the identification and confirmation of the specific nucleotide polymorphism at the 174 and 308 position of the IL-6 and TNF-α promoter, respectively. The frequency of the high cytokine producing genotypes in the cohort was compared to established controls and the statistical significance determined by the two-tailed Fishers exact test. The GG genotype of the IL-6/−174 polymorphism was present in 32 of 73 (44%) of affected patients versus 80 of 250 (32%) historical controls of the control population (p =0.0698) while the AA genotype of the TNF-α/−308 polymorphism was found in 8 of 73 AA patients (11%) and in only 9 of 354 historical controls (2.5%) (p= 0.0034). Three of 73 AA patients had both gene polymophisms p<0.0001. Two patients’ BM was cultured and ELISA performed for TNF-α as part of a larger study, which included 20 normal controls and 30 patients with marrow failure; both of these patients demonstrated significant elevations in TNF-α. In conclusion, we showed that some patients with acquired bone marrow failure have cytokine gene polymophisms which are linked to high production of pro-inflammatory cytokines, particularly TNF-α.

Download Full-text