Abnormal function of B lymphocytes from peripheral blood of multiple myeloma patients. Lack of correlation between the number of cells potentially able to secrete immunoglobulin M and serum immunoglobulin M levels.

Pilarski, Linda M.; Ruether, Bernard A.; Mant, Michael J.

doi:10.1172/jci111921

Cited by 26 publications

(21 citation statements)

References 32 publications

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“…To assess the clonogenic potential of fractionated or unfractionated thymocytes, cells were cultured at limiting dilution in microtiter plates to quantitate the frequency of cells able to give rise to a clone using the method of Moretta et al [28,29] as described previously [30]. Unfractionated or antibodydepleted fractions of thymus were cultured at a range of cell concentrations (1-1000 cells/well) in RPMI plus FCS supplemented with 2 @ml concanavalin A (Con A), 1 % human AB serum [31], 25 mM Hepes and a final concentration of 0.31% sodium hydrogen carbonate.…”

Section: Limiting Dilution Culture Of Thymocytesmentioning

confidence: 99%

“…Unfractionated or antibodydepleted fractions of thymus were cultured at a range of cell concentrations (1-1000 cells/well) in RPMI plus FCS supplemented with 2 @ml concanavalin A (Con A), 1 % human AB serum [31], 25 mM Hepes and a final concentration of 0.31% sodium hydrogen carbonate. All cultures were supplemented with 10% T cell growth factors (TCGF) derived from PBL stimulated with 2 pg/ml Con A for 3 days [30], and lo5 PBL irradiated with 7500 rad as feeder cells. Cultures were incubated at 37 "C in 10% CO2/air for 2-3 weeks and scored by microscopic inspection for clonal growth.…”

Section: Limiting Dilution Culture Of Thymocytesmentioning

confidence: 99%

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Definition of the thymic generative lineage by selective expression of high molecular weight isoforms of CD45 (T200)

et al. 1989

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Selective expression of CD45 isoforms distinguishes naive and memory T cells in peripheral blood. Paradoxically, although the most recent thymic emigrants are CD45R+ CD45 p180-, the majority of thymocytes are CD45 p180+. Speculating that the small subset of thymocytes selectively expressing only the high molecular weight isoforms of CD45 constitute the thymic generative lineage giving rise to peripheral T cells, we characterized the phenotypic and functional properties of CD45 p180- thymocytes. All cells bearing CD45 p180 were removed by rigorous depletion or all CD45R+ thymocytes were removed in a parallel depletion. CD45R- thymocytes were essentially the same in phenotype and CD4/CD8 subset distribution as unfractionated thymus, and dissimilar to naive peripheral blood lymphocyte (PBL) T cells. In contrast, CD45 p180- thymocytes, mainly CD45R+, were CD1- CD38- pgp 1+, corresponding closely to the phenotype of naive CD45R+ PBL T cells. This subset is enriched in CD4+ or CD8+ single positives, includes a high proportion of CD4-8- thymocytes which are predominantly CD3-, and appears to have a medullary location. Approximately 40%-50% of CD45 p180- thymocytes expressed a high density of CDw29 (4B4), which in the periphery is expressed at high density only on CD45 p180+ memory T cells and at low density on CD45R+ naive T cells. However, the expression of high density CDw29 in the absence of CD45 p180 indicates a close resemblance to fetal lymphocytes and suggests an essential role for CDw29 in both the least and the most mature of T cells. If CD45 p180- thymocytes constitute the generative lineage and CD45 p180+ cells are commited to intrathymic death, then the CD45 p180- subset should have enhanced proliferative potential. By combining depletion methods with a limiting dilution assay for clonogenic potential, we found that 100% of the clonogenic precursors present in unfractionated thymus were CD45R+ CD45 p180- cells. This indicates that the CD45 p180+ majority of thymocytes has a very limited capability for proliferation consistent with a commitment to intrathymic death. The clonogenic potential of CD45 p180- thymocytes indicates a greater functional resemblance to PBL T cells than to CD45 p180+ thymocytes. In so far as clonogenic potential in vitro reflects generative potential in vivo, expression of high molecular weight CD45 isoforms appears to define the generative thymic lineage. Our working hypothesis proposes that expression of CD45 p180 implements the mechanism for eliminating thymocytes with self-reactive receptor specificities.

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Section: Limiting Dilution Culture Of Thymocytesmentioning

confidence: 99%

Section: Limiting Dilution Culture Of Thymocytesmentioning

confidence: 99%

Definition of the thymic generative lineage by selective expression of high molecular weight isoforms of CD45 (T200)

et al. 1989

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“…Indeed, in patients with multiple myeloma/MGUS, it has been reported the existence of an autoimmune inhibitory network leading to the arrest in B-cell differentiation and consequent humoral immune deficiency, 17 possibly sustaining, in this case, the disappearance of IgG OCBs. Such abnormality markedly affected the IgG isotype in our patient, in whom rituximab therapy, in turn, decreased anti-MAG-specific and total IgM levels.…”

Section: Commentmentioning

confidence: 96%

Relapses After Treatment With Rituximab in a Patient With Multiple Sclerosis and Anti–Myelin-Associated Glycoprotein Polyneuropathy

Benedetti¹,

Franciotta²,

Vigo³

et al. 2007

Arch Neurol

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“…Myeloma is a B-cell malignancy, and individuals with myeloma have a reduced level of normal immunoglobulin (serum IgM ∼1.9mg/ml), associated with the suppression of B-cell differentiation that may be explained by an arrest in B-cell maturation [97]. Symptomatic myeloma patients have lower numbers of B-cells compared to age matched controls.…”

Section: The Impact Of Hematopoietic Derived Cells On Myeloma Progresmentioning

confidence: 99%

Dissecting the multiple myeloma-bone microenvironment reveals new therapeutic opportunities

2015

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Multiple myeloma is a plasma cell skeletal malignancy. While therapeutic agents such as bortezomib and lenalidomide have significantly improved overall survival, the disease is currently incurable with the emergence of drug resistance limiting the efficacy of chemotherapeutic strategies. Failure to cure the disease is in part due to the underlying genetic heterogeneity of the cancer. Myeloma progression is critically dependent on the surrounding microenvironment. Defining the interactions between myeloma cells and the more genetically stable hematopoietic and mesenchymal components of the bone microenvironment is critical for the development of new therapeutic targets. In this review, we discuss recent advances in our understanding of how microenvironmental elements contribute to myeloma progression and therapeutically, how those elements can or are currently being targeted in a bid to eradicate the disease.

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Abnormal function of B lymphocytes from peripheral blood of multiple myeloma patients. Lack of correlation between the number of cells potentially able to secrete immunoglobulin M and serum immunoglobulin M levels.

Cited by 26 publications

References 32 publications

Definition of the thymic generative lineage by selective expression of high molecular weight isoforms of CD45 (T200)

Definition of the thymic generative lineage by selective expression of high molecular weight isoforms of CD45 (T200)

Relapses After Treatment With Rituximab in a Patient With Multiple Sclerosis and Anti–Myelin-Associated Glycoprotein Polyneuropathy

Dissecting the multiple myeloma-bone microenvironment reveals new therapeutic opportunities

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