Memory Stem T Cells in Autoimmune Disease: High Frequency of Circulating CD8+Memory Stem Cells in Acquired Aplastic Anemia

Abstract Background Hematopoietic stem cells (HSCs) harboring PIGA mutations acquire a survival advantage under immune pressure compared to normal HSCs in patients with acquired aplastic anemia (AA). Cytotoxic T cells (CTLs) specific to glycosylphosphatidylinositol-anchored proteins (GPI-APs) are reportedly involved in this survival advantage, because PIGA mutant HSCs cannot present GPI-AP-derived peptides via class I HLAs. However, there is no convincing evidence that CTLs specific to GPI-AP-derived peptides are involved in the “escape” hematopoiesis by PIGA mutant HSCs. We recently demonstrated that 31.4-99.4% HLA-A allele-lacking leukocytes (HLA-LLs) were detectable in approximately 13% of AA patients as a result of escape hematopoiesis by HSCs with uniparental disomy in the short arm of chromosome 6, and that some patients possessed both GPI-AP-deficient (GPI-AP-) leukocytes and HLA-LLs (Katagiri, et al. Blood 2011). We hypothesized that if GPI-AP-derived peptides serve as a target for CTLs that elicit the development of AA, HLA-LLs may always be detectable only in the GPI-AP+ leukocyte population, because PIGA mutant HSCs do not require the lack of HLA class Is for the escape from the attack by GPI-AP peptide-specific CTLs. Objectives and Methods To examine this hypothesis, the GPI-AP expression was analyzed in various leukocyte lineages in 32 (nine at diagnosis and 23 previously treated) AA patients possessing HLA-LLs by a flow cytometry (FCM) analysis with liquid fluorescent aerolysin. Results A total of 0.01%-50% GPI-AP- granulocytes (GPI-AP- Gs) were detected in 22 (69%) of the 32 HLA-LLs (+) patients. Of the 22 patients possessing both HLA-LLs and increased GPI-AP- Gs, HLA-LLs were detectable in GPI-AP+ cells alone in 19 patients (86%). However, in the remaining three patients, HLA-LLs were shown in both GPI-AP+ and GPI-AP- populations. To determine which mutation occurs first in HSCs with a PIGA mutation and 6pUPD, the lineage diversity of GPI-AP- HLA-LLs was determined in the three patients. In two of the three patients, the lineage diversity of GPI-AP- cells (G/monocytes (M)/T cells (T)/B cells (B)/NK cells (NK)) and G/M/T) was greater than that of the HLA-A-lacking cells (G/M/B/NK and G/M) suggesting that PIGA mutations occurred earlier in the maturation of HSCs than did 6pUPD. The lineage diversity was the same in the GPI-AP- cells and HLA-LLs in one patient Conclusions The presence of HLA-LLs in the GPI-AP- leukocyte population and lower lineage diversity in HLA-LLs than GPI-AP- leukocytes suggest that CTLs specific to GPI-APs are not involved in the escape of PIGA mutant HSCs in AA, and that other mechanisms, such as a lower sensitivity to myelosuppressive cytokines than wild-type HSCs, may contribute to the survival advantage of PIGA mutant HSCs. Disclosures: No relevant conflicts of interest to declare.

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GPI-AP Deficient Cells Detected Exclusively in T Cells in Patients with Aplastic Anemia: Evidence against An Escape Mechanism for the Initial Proliferation of PIG-AMutant Hematopoietic Stem Cells.

Blood ◽

10.1182/blood.v114.22.3197.3197 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3197-3197

Author(s):

Takamasa Katagiri ◽

Zhirong Qi ◽

Yu Kiyu ◽

Naomi Sugimori ◽

J. Luis Espinoza ◽

...

Keyword(s):

Stem Cells ◽

T Cells ◽

Immune System ◽

T Cell ◽

Hematopoietic Stem Cells ◽

Aplastic Anemia ◽

Effector Memory ◽

Hematopoietic Stem ◽

Escape Theory ◽

Effector Memory Cells

Abstract Abstract 3197 Poster Board III-134 Small populations of glycosylphosphatidylinositol-anchored protein (GPI-AP)-deficient blood cells are often detectable in the peripheral blood (PB) of patients with aplastic anemia (AA) and refractory anemia (RA) of myelodysplastic syndromes defined by the FAB classification. Such PNH-type cells are thought to be derived from PIG-A mutant hematopoietic stem cells (HSCs) that avoid the immunological attack against HSCs. Inefficient T cell responses to PNH-type cells were indeed demonstrated by a murine study. However, there is no direct evidence in support of the escape theory concerning the expansion of PIG-A mutant HSCs in such patients with bone marrow (BM) failure. If the escape theory is true, the PNH-type cells should be detected in myeloid cells derived from HSCs that are targeted by the immune system attack. The PB of 527 patients with BM failure was examined for the presence of GPI-AP deficient cells in various lineages of cells including granulocytes, erythrocytes, monocytes, T cells, B cells, and NK cells using high sensitivity flow cytometry to verify this hypothesis. PNH-type cells were detectable in at least one lineage of cells from 228 (43%) patients. Although most of the positive patients showed PNH-type cells in two or more lineages including granulocytes or monocytes, 14 patients (13 with AA and 1 with amegakaryocytic thrombocytopenia) displayed PNH-type CD48-CD55-CD59- cells only in T cells at a frequency of 0.003-0.3% of the total T cells (Figure). The PNH-type T cells were undetectable in any of 25 healthy individuals. The CD48-CD55-CD59- T cells consisted of predominantly effector memory and terminal effector memory cells with naïve phenotype cells. The phenotypic pattern of the PNH-type T cells was very similar to that of CD48-CD55-CD59- T cells from 11 patients with florid PNH but was different from that of CD48-CD55-CD59- T cells (central and effector memory cells alone) detected in 4 marrow transplant recipients who received anti-CD52 antibody (alemtuzumab) therapy as conditioning. PIG-A gene analyses of CD48-CD55-CD59- T cells revealed a single mutation in 2 patients with PNH-type T cells alone, while two different mutations were revealed in 2 patients treated with alemtuzumab. BM failure patients with PNH-type T cells alone and other BM failure patients possessing PNH-type granulocytes or monocytes showed similar clinical features characterized by predominant thrombocytopenia and good response to immunosuppressive therapy, thus suggesting an increase in the number of PNH-type cells in both groups to be associated with a similar immune pathophysiology. The escape theory cannot account for the presence of PNH-type cells exclusively in T cells in immune-mediated BM failure because T cell precursors are not the target of the immune system attack in AA. Therefore, mechanisms other than the escape theory must be considered for the initial proliferation of PIG-A mutant HSCs associated with the development of AA, such as preferential activation of dormant PIG-A mutant HSCs or T cell precursors due to the deficiency of GPI-APs that transmit negative signal Disclosures No relevant conflicts of interest to declare.

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Impaired immunomodulatory ability of bone marrow mesenchymal stem cells on CD4+ T cells in aplastic anemia

Results in Immunology ◽

10.1016/j.rinim.2012.07.002 ◽

2012 ◽

Vol 2 ◽

pp. 142-147 ◽

Cited By ~ 14

Author(s):

Jianping Li ◽

Shihong Lu ◽

Shaoguang Yang ◽

Wen Xing ◽

Jianming Feng ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

T Cells ◽

Mesenchymal Stem Cells ◽

Aplastic Anemia ◽

Cd4 T Cells ◽

Marrow Mesenchymal Stem Cells

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Human Olfactory Mesenchymal Stem Cells Are a Novel Candidate for Neurological Autoimmune Disease

Frontiers in Pharmacology ◽

10.3389/fphar.2021.770884 ◽

2021 ◽

Vol 12 ◽

Author(s):

Chongjun Xiao ◽

Di Lu ◽

Jinshuo Chen ◽

Xiaoyan Chen ◽

Huizhu Lin ◽

...

Keyword(s):

Stem Cells ◽

T Cells ◽

Mesenchymal Stem Cells ◽

Treatment Group ◽

Autoimmune Disease ◽

Functional Recovery ◽

Therapeutic Option ◽

Control Group ◽

Immune Disorder ◽

Ifn Γ

Background: Human olfactory mesenchymal stem cells (OMSC) have become a novel therapeutic option for immune disorder or demyelinating disease due to their immunomodulatory and regenerative potentials. However, the immunomodulatory effects of OMSC still need to be elucidated, and comparisons of the effects of different MSCs are also required in order to select an optimal cell source for further applications.Results: In animal experiments, we found neural functional recovery and delayed EAE attack in the OMSC treatment group. Compared with umbilical cord–derived mesenchymal stem cells (UMSC) treatment group and the control group, the OMSC treatment group had a better neurological improvement, lower serum levels of IFN-γ, and a lower proportion of CD4+IFN-γ+ T splenic lymphocyte. We also observed OMSC effectively suppressed CD4+IFN-γ+ T cell proportion in vitro when co-cultured with human peripheral blood–derived lymphocytes. The OMSC-mediated immunosuppressive effect on human CD4+IFN-γ+ T cells was attenuated by blocking cyclooxygenase activity.Conclusion: Our results suggest that OMSC treatment delayed the onset and promoted the neural functional recovery in the EAE mouse model possibly by suppressing CD4+IFN-γ+ T cells. OMSC transplantation might become an alternative therapeutic option for neurological autoimmune disease.

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Emerging Cellular Therapies for Anti-myeloperoxidase Vasculitis and Other Autoimmune Diseases

Frontiers in Immunology ◽

10.3389/fimmu.2021.642127 ◽

2021 ◽

Vol 12 ◽

Author(s):

Dragana Odobasic ◽

Stephen R. Holdsworth

Keyword(s):

Stem Cells ◽

T Cells ◽

Dendritic Cells ◽

Autoimmune Disease ◽

Regulatory T Cells ◽

Adverse Effects ◽

Autoimmune Diseases ◽

Cellular Therapies ◽

Tolerogenic Dendritic Cells ◽

Life Threatening

Anti-myeloperoxidase vasculitis (MPO-AAV) is a life-threatening autoimmune disease which causes severe inflammation of small blood vessels, mainly in the kidney. As for many other autoimmune diseases, current treatments, which consist of general immunosuppressants, are partially effective, toxic and broadly immunosuppressive, causing significant and serious adverse effects in many patients. Therefore, there is an urgent need for more targeted and less harmful therapies. Tolerogenic dendritic cells, regulatory T cells and stem cells have emerged as attractive, new and safer options for the treatment for various autoimmune diseases due to their unique and selective immunosuppressive capacity. In this review, we will discuss how these cellular therapies offer potential to become novel and safer treatments for MPO-AAV.

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