BETA 2 MICROGLOBULIN RESEARCH

Killing tumor cells through their surface beta(2)-microglobulin

noreply@blogger.com (Unknown) — Fri, 12 Feb 2010 18:33:00 +0000

Targeted antibody-based therapy has been used successfully to treat cancers. Recent studies have demonstrated that tumor cells treated with antibodies specific for beta 2-microglobulin (beta(2)M) or major histocompatibility complex (MHC) class I molecules undergo apoptosis in vitro and in vivo (mouse models).

Antibodies against beta(2)M or MHC class I induce tumor cell apoptosis by 1) recruiting MHC class I molecules to lipid rafts and activating LYN kinase and the signal-transducing enzyme phospholipase C-gamma2-dependent c-Jun N-terminal kinase signaling pathway and 2) expelling interleukin 6 and insulin-like growth factor 1 receptors out of lipid rafts and inhibiting the growth and survival factor-induced activation of the phosphatidylinositol 3-kinase/Akt and extracellular signal-related kinase pathways.

Consequently, mitochondrial integrity is compromised, and the caspase-9-dependent cascade is activated in treated tumor cells. However, although beta(2)M and MHC class I are expressed on normal hematopoietic cells, which is a potential safety concern, the monoclonal antibodies were selective to tumor cells and did not damage normal cells in vitro or in human-like mouse models. These findings suggest that targeting beta(2)M or MHC class I by using antibodies or other agents offers a potential therapeutic approach for beta(2)M/MHC class I-expressing malignancies.

Cancer. 2010 Feb 8.

Killing tumor cells through their surface beta(2)-microglobulin or major histocompatibility complex class I molecules.
Yang J, Yi Q.

Department of Lymphoma and Myeloma, Division of Cancer Medicine, Center for Cancer Immunology Research, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.

Levels of beta 2 microglobulin have a prognostic relevance for patients with myelodysplastic syndrome with regard to survival and the risk of trans

noreply@blogger.com (Unknown) — Wed, 19 Aug 2009 19:25:00 +0000

We evaluated the relevance of beta 2 microglobulin (B2M) plasma concentration in 109 patients with myelodysplastic syndrome (MDS) from the Duesseldorf registry. Sixty-five patients with B2M level ≥2mg/dl showed a significantly lower overall survival time with a median of 23 in comparison to 61 months for 44 patients with B2M below 2mg/dl. The risk of AML evolution was higher in patients with B2M≥2mg/dl. Using multivariate analysis we found the B2M level at the time of diagnosis to be an independent prognostic parameter for survival and for the risk of developing AML in high-risk MDS patients

Leukemia Research: Department of Hematology, Oncology and Clinical Immunology, Heinrich-Heine-University Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany

Volume 33, Issue 2, Pages 232-236 (February 2009)

Beta2-microglobulin is a better predictor of treatment-free survival in patients with chronic lymphocytic leukaemia if adjusted according to glomerula

noreply@blogger.com (Unknown) — Thu, 21 May 2009 15:42:00 +0000

ABSTRACT
Even in the era of newer and sophisticated prognostic markers, beta2-microglobulin (B2M) remains a simple but very powerful predictor of treatment-free survival (TFS) and overall survival (OS) in patients with chronic lymphocytic leukaemia (CLL). However, B2M levels are heavily influenced by the patient's glomerular filtration rate (GFR) and this study aimed to evaluate whether GFR-adjusted B2M (GFR-B2M) had improved prognostic value compared to unadjusted B2M in a cohort of over 450 consecutive CLL patients from two separate institutions.

Multivariate analysis identified a significantly shorter TFS in patients who were ZAP-70 + (P < 0·001), with increased GFR-B2M (P < 0·001), and del(11q) or del(17p) as detected by fluorescence in situ hybridization (FISH; P < 0·001). When OS was evaluated by multivariate analysis, age 65 years or older (P < 0·001) and poor risk FISH abnormalities (P < 0·001) had a confirmed adverse prognostic impact, but the predictive value of GFR-B2M was lost in the validation analysis.

In all survival models, B2M did not attain independent significance unless GFR-B2M was eliminated from the analysis. In conclusion, GFR-B2M is a better predictor of TFS than unadjusted B2M in CLL patients.

Servei d'Hematologia, Hospital de la Santa Creu i Sant Pau, C/Sant Antoni Maria Claret 167, 08025 Barcelona, Spain.

The Prognostic Significance of Serum β2 Microglobulin Levels in Acute Myeloid Leukemia and Prognostic Scores Predicting Survival: Analysis of 1,180 Pa

noreply@blogger.com (Unknown) — Fri, 08 Aug 2008 15:15:00 +0000

Purpose: Serum B2 microglobulin (B2M) is prognostic in other hematologic malignancies; therefore, we evaluated its prognostic significance in acute myeloid leukemia (AML).

Experimental Design: Multivariate analyses were used to examine the effect of pretreatment Serum B2 microglobulin (b2M) levels on clinical outcomes in patients with AML. beta 2 microglobulin B2M was associated with poorer survival in older but not younger patients. We thus fit separate Cox survival models in patients above and below age 60 years treated with remission induction therapy containing high-dose cytarabine (n = 1,280). In each age group, 50% of the patients were used to develop the model, which was tested in the other 50%. Resampling methods were also used to validate the independent prognostic significance of covariates.

Results: In patients 60 years or older (n = 591), poorer risk cytogenetics; poorer performance status; and higher levels of B2M, uric acid, and lactate dehydrogenase were each found to independently predict shorter survival and formed the basis of a scoring system. A similar approach was used in patients younger than 60 years (n = 589), with poorer risk cytogenetics, poorer performance status, older age, higher hemoglobin level, and higher leukocyte count predicting a shorter survival and forming the basis of the scoring system. Higher β2M levels were an adverse independent factor for response, survival, relapse-free survival, and event-free survival in older but not in younger patients.

Conclusions: Serum β2M levels can help predict outcome in patients 60 years with untreated AML, and their use is strongly encouraged.

The Prognostic Significance of Serum β2 Microglobulin Levels in Acute Myeloid Leukemia and Prognostic Scores Predicting Survival: Analysis of 1,180 Pa

noreply@blogger.com (Unknown) — Thu, 24 Jul 2008 19:26:00 +0000

Purpose:
Serum β2 microglobulin (β2M) is prognostic in other hematologic malignancies; therefore, we evaluated its prognostic significance in acute myeloid leukemia (AML).

Experimental Design:
Multivariate analyses were used to examine the effect of pretreatment serum β2M levels on clinical outcomes in patients with AML. β2 microglobulin (β2M) was associated with poorer survival in older but not younger patients. We thus fit separate Cox survival models in patients above and below age 60 years treated with remission induction therapy containing high-dose cytarabine (n = 1,280). In each age group, 50% of the patients were used to develop the model, which was tested in the other 50%. Resampling methods were also used to validate the independent prognostic significance of covariates.

Results:
In patients 60 years or older (n = 591), poorer risk cytogenetics; poorer performance status; and higher levels of β2 microglobulin (β2M), uric acid, and lactate dehydrogenase were each found to independently predict shorter survival and formed the basis of a scoring system. A similar approach was used in patients younger than 60 years (n = 589), with poorer risk cytogenetics, poorer performance status, older age, higher hemoglobin level, and higher leukocyte count predicting a shorter survival and forming the basis of the scoring system. Higher β2M levels were an adverse independent factor for response, survival, relapse-free survival, and event-free survival in older but not in younger patients.

Conclusions:
Serum β2 microglobulin (β2M) levels can help predict outcome in patients 60 years with untreated AML, and their use is strongly encouraged.

Molecular differences b/t divergent responses of ovalbuminspecific CD4 T cells to alumprecipitated ovalbumin compared toovalbumin expressed Salmonella

noreply@blogger.com (Unknown) — Thu, 17 Jul 2008 17:02:00 +0000

CD4 T helper (Th) cell differentiation defined by in vitro cytokine-directed culture systems leaves major gaps in our knowledge of the mechanisms driving divergent Th differentiation. This is evident from our analysis of the response of mouse ovalbumin-specific CD4 T cells to different forms of ovalbumin that induce markedly distinct responses in vivo. We show that live attenuated ovalbumin-expressing Salmonella (SalOVA) induce Th1-associated T-bet and IFN-γ. Conversely, alum-precipitated ovalbumin (alumOVA) induces the Th2-associated GATA-3 and IL-4. The early diversity occurring within these CD4 T cells isolated 3 days after immunization was assessed using real-time RT-PCR microfluidic cards designed with 384 selected genes. The technique was validated both at the population and single cell levels at different stages of the responses, showing β2-microglobulin to be a more stably expressed reference mRNA than either β-actin or 18S RNA. SalOVA was then shown selectively to induce the OVA-specific CD4 T cells to produce many chemokines and pro-inflammatory cytokines, contrasting with alumOVA-induced cells that only produced a few Th2-associated cytokines. Several cytokines and features associated with follicular helper functions were induced in the OVA-specific CD4 T cells by both antigens. Finally, IL-17RB is strongly associated with OVA-specific CD4 T cells responding to alumOVA, suggesting that alum may promote Th2 immune response through a role for the IL-25/IL-17RB pathway.

ARTICLE

Reduction in β2-Microglobulin With Super-flux Versus High-flux Dialysis Membranes: Results of a 6-Week, Randomized, Double-blind, Crossover Trial

noreply@blogger.com (Unknown) — Tue, 01 Jul 2008 20:46:00 +0000

Background
Uremic toxicity is a major concern in the dialysis population. There is keen interest in techniques that increase the removal of larger uremic molecules. We examined the short-term impact of a new, more porous, super-flux Helixone membrane (FX-E) versus the conventional high-flux Helixone membrane (FX-60) on β2-microglobulin (Beta 2 Microglobulin) reduction and nutritional and inflammatory parameters.

Study Design
Randomized, double blind, crossover, pilot trial.

Setting & Participants
A single freestanding dialysis center. 30 stable hemodialysis patients.

Intervention
Patients were treated with FX-60 and FX-E membranes for a treatment period of 6 weeks each, with a 2-week washout period in between.

Outcome & Measurements
Primary outcome was change in β2-microglobulin (Beta 2 Microglobulin) concentrations from baseline to end of treatment. Serum samples were obtained predialysis and postdialysis at 0, 2, and 6 weeks, and dialysate albumin samples were collected continuously throughout dialysis sessions.

Results
Mean postdialysis β2M concentrations at the end of 6 weeks of treatment were 6.73 mg/L for FX-E versus 8.22 mg/L for FX-60, which was significantly lower overall by 0.69 mg/L (95% confidence interval [CI], −1.09 to −0.29; P = 0.001). β2M reduction ratios were greater overall with FX-E by 4.83% (95% CI, 2.78 to 6.89; P < 0.001), with mean values of 57% for FX-60 versus 66% for FX-E at the end of treatment. Median dialysate albumin loss with FX-E was 1.23 g (range, 0.22 to 4.83 g) compared with 0.17 g (range, 0.0017 to 2.69 g) with FX-60, which was greater by 1.52 g (95% CI, 1.11 to 1.93; P < 0.001). Serum albumin concentrations were slightly lower with FX-E by 0.1 g/dL (0.55 g/L; 95% CI, −1.04 to −0.07; P = 0.03), but prealbumin concentrations were not significantly different at 8.53 mg/L (95% CI, −23.76 to 6.71; P = 0.3). There were no differences in inflammatory cytokine concentrations or small-solute removal.

Limitations
Short-term pilot study.

Conclusion
In this stable dialysis population, removal of β2-microglobulin (Beta 2 Microglobulin) was more efficient with the Helixone super-flux FX-E membrane, with only a small decrease in albumin concentrations despite increased albumin loss. Large trials with longer treatment periods are required to evaluate the impact of the FX-E membrane on clinical outcomes.

ARTICLE

Cloning and characterization of ovine β2-microglobulin cDNAs

noreply@blogger.com (Unknown) — Mon, 16 Jun 2008 20:20:00 +0000

Beta-2-microglobulin (β2m) is the light chain of the major histocompatibility complex (MHC) class I cell surface heterodimer. β2m is well conserved across most species with few polymorphisms seen within species. The aims of this study were to clone and express ovine β2m and investigate if allelic variation of ovine β2m exists. Ovine β2m clones were isolated from five sheep of three breeds by reverse-transcription polymerase chain reaction (RT-PCR). Sequence analysis showed that four ovine β2m sequences were obtained. Within breeds and individual animals there was evidence of allelic variation of ovine β2m. An expression system was established to express one of the alleles with an ovine MHC class I cDNA clone in human embryo kidney cells (HEK293) and quail cells (QT35). Transfection experiments showed that ovine β2m was expressed and directed the expression of ovine MHC class I heavy chain to the cell surface of the transfected cells. Both bovine and human β2m supported ovine MHC class I heavy chain cell surface expression.

Changxin Wua, Ian McConnella and Barbara Blacklaws

ARTICLE

Beta-2-microglobulin level predicts outcome following autologous hematopoietic stem cell transplantation in patients with multiple myeloma

noreply@blogger.com (Unknown) — Fri, 01 Feb 2008 19:10:00 +0000

Despite the widespread use of high-dose therapy combined with autologous hematopoietic stem cell transplantation (autoHSCT), the outcomes of multiple myeloma (MM) treatment remain variable. The aim of this study was to define pretransplantation factors that influence outcomes following autoHSCT in patients with MM. Eighty-one MM patients, aged 51 years (range 31-70 years), undergoing first autoHSCT were included in the analysis. Thirty patients were in complete remission and 51 were in partial remission.

The conditioning regimen was based mainly on melphalan (200 mg/m(2) intravenous [iv]). The following factors were tested for their prognostic significance: beta-2-microglobulin (B2M), lactate dehydrogenase , monoclonal protein level, bone marrow plasma cell percentage (PL), hemoglobin level, age, interval from diagnosis to autoHSCT, and number of transplanted CD34-positive cells.

The transplant-related mortality at day 100 was 3.7% (3/81). The incidence of progression at 9.2 years was 71% for patients with elevated B2M, and 32% for those where B2M was within normal limits (P = .02.) The probability of PFS was decreased for patients with B2M > or = versus < normal limits (29% vs 68%; P = .02) and PL > or = versus < 5% (0% vs 45%; P = 0.03).

In a multivariate analysis B2M remained the only factor associated with increased risk of progression (relative risk [RR] = 3.3; P = .03) and reduced probability of PFS (RR = 3.3; P = .03). We concluded that B2M level measured at first autoHSCT was a useful predictor for progression and PFS in MM patients.

Stella-Holowiecka B, Czerw T, Holowiecka-Goral A, Giebel S, Wojnar J, Holowiecki J.
Department of Hematology and Bone Marrow Transplantation, Silesian Medical University, Katowice, Poland. klinem@sum.edu.pl.Transplant Proc. 2007 Nov;39(9):2893-7

What Is Beta 2 Microglobulin

noreply@blogger.com (Unknown) — Wed, 19 Dec 2007 22:44:00 +0000

Beta 2 microglobulin is a component of major histocompatibility complex (MHC) class I molecules, which are present on almost all cells of the body red blood cells are a notable exception. Beta 2 microglobulin lies lateral to the alpha 3 chain on the cell surface.

Beta 2 microglobulin is a small protein normally found on the surface of many cells, including lymphocytes, and in small amounts in the blood and urine . Testing is done primarily when evaluating a person for certain kinds of cancer affecting white blood cells including chronic lymphocytic leukemia , non-Hodgkin's lymphoma, and multiple myeloma or kidney disease .

beta 2-Microglobulin (beta 2M), an interesting and underutilized metabolite, can be used in assessing renal function , particularly in kidney-transplant recipients and in patients suspected of having renal tubulointerstitial disease . It also can serve as a nonspecific but relatively sensitive marker of various neoplastic, inflammatory, and infectious conditions.(1)

(1) Annals of Clinical and Laboratory Science , Vol 20, Issue 3, 163-168