Impaired bone marrow hematopoietic progenitor cell function in rheumatoid arthritis patients candidated to autologous hematopoietic stem cell transplantation

Porta, Camillo; Caporali, Roberto; Epis, Oscar Massimiliano; Ramaioli, I; Invernizzi, Rosangela; Rovati, B.; Comolli, Giuditta; Danova, Marco; Montecucco, Carlomaurizio

doi:10.1038/sj.bmt.1704407

Cited by 26 publications

(23 citation statements)

References 49 publications

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“…Given the pleiotropic effects of TNF-a, this complexity is not unexpected and is underscored by our observation of increased fractions of apoptotic and dead stem cells, granulocytoid cells and all erythroid precursors. Previously, TNF-a has been implicated in increased apoptosis in stem cells (16), lymphoid cells (37), myeloid cells (44), and erythroid precursors (16). Finally, in keeping with the mild microcytic hypochromic anemia and effect on reticulocyte hemoglobin parameters, observed in the peripheral blood, we also observed changes in the expression of transferrin receptors in the ProEB.…”

Section: Discussionsupporting

confidence: 52%

Myelodysplasia and anemia of chronic disease in human tumor necrosis factor‐α transgenic mice

Capocasale¹,

Makropoulos²,

Achuthanandam³

et al. 2008

Cytometry Pt A

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TNF-a is a pleitropic cytokine that expresses both pro-and anti-inflammatory activity and transgenic mice expressing human tumor necrosis factor-a (TNF-a) exhibit a progressive polyarthritis that models rheumatoid arthritis (RA). One of the common comorbidities of RA is anemia of chronic disease (ACD). The purpose of these experiments was to study the changes in the bone marrow and peripheral blood that accompany polyarthritis in TNF-a transgenic mice in an effort to better understand the pathogenesis of myelodysplasia and ACD. Polychromatic cytometry, hematology and serum cytokine analysis were used to study the pathogenesis of ACD in human TNF-a transgenic mice. Our hematological evaluation revealed a mild, compensated, microcytic hypochromic anemia, and monocytosis. In the bone marrow, we observed alterations in cell kinetics, decreased relative expression of transferrin receptor and increased apoptosis and cell death in several late precursor cell populations. Although significant levels of human TNF-a were found in the serum, neither change in serum murine erythropoietin nor any significant difference observed in serum levels of murine IL-b, IL-5, IL-6, IL-10, IL-12(p70), IL-17, TNF-a, IFNg, GM-CSF, MIP-1aJE, MCP-5 was observed. Tg197 mice develop a compensated, microcytic, hypochromic anemia, and a functional iron deficiency by 9 weeks of age. Changes in peripheral blood are reflected in alterations in cell kinetics, transferrin receptor expression and markedly increased apoptosis and cell death in the bone marrow indicating that TNF-a may contribute to myelodysplasia in ACD. Moreover, since human TNF-a can interact only with murine TNFR1, our data suggest that TNFR1 may play an important role in the development of ACD. '

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Section: Discussionsupporting

confidence: 52%

Myelodysplasia and anemia of chronic disease in human tumor necrosis factor‐α transgenic mice

Capocasale¹,

Makropoulos²,

Achuthanandam³

et al. 2008

Cytometry Pt A

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“…Progenitor cells have also been isolated from synovial fluid (34). Support for a reduction of the HPC pool in RA comes from studies describing reduced numbers of BM CD34ϩ cells and reduced recovery of CD34ϩ populations in RA patients undergoing BM transplantation (22,23). Finally, endothelial precursor cells are markedly reduced in RA patients, suggesting an age-inappropriate demise affecting several CD34ϩ subpopulations (19).…”

Section: Discussionmentioning

confidence: 99%

“…Specifically, in peripheral blood stem cell harvests, CD34ϩ cells were found to be reduced to 50% in RA patients as compared with healthy controls (22). Significantly lower percentages of CD34ϩ BM cells have been reported in RA patients who were candidates for autologous HSC transplantation (23).…”

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confidence: 94%

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Defective proliferative capacity and accelerated telomeric loss of hematopoietic progenitor cells in rheumatoid arthritis

Colmegna

Díaz-Borjón

Fujii

et al. 2008

Arthritis & Rheumatism

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Objective. In rheumatoid arthritis (RA), telomeres of lymphoid and myeloid cells are ageinappropriately shortened, suggesting excessive turnover of hematopoietic precursor cells (HPCs). The purpose of this study was to examine the functional competence (proliferative capacity, maintenance of telomeric reserve) of CD34؉ HPCs in RA.Methods. Frequencies of peripheral blood CD34؉,CD45؉ HPCs from 63 rheumatoid factorpositive RA patients and 48 controls matched for age, sex, and ethnicity were measured by flow cytometry. Proliferative burst, cell cycle dynamics, and induction of lineage-restricted receptors were tested in purified CD34؉ HPCs after stimulation with early hematopoietins. Telomere sequences were quantified by real-time polymerase chain reaction. HPC functions were correlated with the duration, activity, and severity of RA as well as its treatment.Results. In healthy donors, CD34؉ HPCs accounted for 0.05% of nucleated cells; their numbers were strictly age dependent and declined at a rate of 1.3% per year. In RA patients, CD34؉ HPC frequencies were age-independently reduced to 0.03%. Upon growth factor stimulation, control HPCs passed through 5 replication cycles over 4 days. In contrast, RA-derived HPCs completed only 3 generations. Telomeres of RA CD34؉ HPCs were age-inappropriately shortened by 1,600 bp.

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“…Por outro lado, um estudo europeu com pacientes com AR candidatos a TCTH mostrou, ao lado de reduzido número de progenitores hematopoéticos na medula óssea dos pacientes, também uma redução da função hematopoética e aumento da apoptose nas células progenitoras mais primitivas. Esses dados, ao contrário do estudo anterior, são preditivos de dificuldades de mobilização e enxertia em pacientes com AR submetidos a TCTH autó-logo (46) . 2) No segundo estudo, foram comparadas as doses de 5 e 10µg/kg/d de G-CSF, isoladamente, para mobilização de CTH.…”

Section: Artrite Reumatóide Do Adultounclassified

Transplante de células-tronco hematopoéticas em doenças reumáticas parte 1: experiência internacional

Voltarelli¹,

Stracieri²,

Soga³

et al. 2005

Rev. Bras. Reumatol.

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RESUMONesta revisão, discutem-se os resultados dos transplantes de células-tronco hematopoéticas (TCTH) para doenças reumáticas graves e refratárias à terapia convencional realizados no exterior. Revêem-se brevemente as bases clínicas e experimentais para a realização desses transplantes e os resultados internacionais obtidos em lúpus eritematoso sistêmico (LES) (33/50 remissões completas no registro europeu, com dez recidivas posteriores e 12 óbitos; 41/45 remissões duradouras em um centro americano, com dois óbitos pós-mobilização e quatro óbitos pós-transplante), artrite reumatóide (AR) do adulto (58/73 remissões parciais com 85% de recidivas posteriores e apenas um óbito no registro europeu), artrite idiopática juvenil (AIJ) (18/34 remissões duradouras e cinco óbitos no registro europeu), esclerose sistêmica (ES) (46/50 respostas em um estudo europeu multicêntrico, com 35% de recidivas e 23% de mortalidade, enquanto num estudo americano, houve quatro óbitos e duas pneumopatias progressivas dentre 19 pacientes e melhora cutânea e da qualidade de vida em todos os sobreviventes) e em uma miscelânea de outras doenças, incluindo as vasculites (9/15 respostas completas no registro europeu). Conclui-se que, na experiência internacional, o TCTH autólogo induz remissões prolongadas na maioria das doenças graves e refratárias em que foi utilizado, com exceção da AR do adulto, justificando o início de estudos prospectivos randomizados comparando-o com a terapia convencional otimizada.

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Impaired bone marrow hematopoietic progenitor cell function in rheumatoid arthritis patients candidated to autologous hematopoietic stem cell transplantation

Cited by 26 publications

References 49 publications

Myelodysplasia and anemia of chronic disease in human tumor necrosis factor‐α transgenic mice

Myelodysplasia and anemia of chronic disease in human tumor necrosis factor‐α transgenic mice

Defective proliferative capacity and accelerated telomeric loss of hematopoietic progenitor cells in rheumatoid arthritis

Transplante de células-tronco hematopoéticas em doenças reumáticas parte 1: experiência internacional

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