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T-cell number and subtype influence the disease course of primary chronic lymphocytic leukaemia xenografts in alymphoid mice.

Oldreive CE, Skowronska A, Davies NJ, Parry H, Agathanggelou A, Krysov S, Packham G, Rudzki Z, Cronin L, Vrzalikova K, Murray P, Odintsova E, Pratt G, Taylor AM, Moss P, Stankovic T - Dis Model Mech (2015)

Bottom Line: Chronic lymphocytic leukaemia (CLL) cells require microenvironmental support for their proliferation.This can be recapitulated in highly immunocompromised hosts in the presence of T cells and other supporting cells.Thus, a greater understanding of the interaction between CLL and T cells could improve their utility.

View Article: PubMed Central - PubMed

Affiliation: School of Cancer Sciences, Department of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, UK.

No MeSH data available.


Related in: MedlinePlus

Engrafted T cells reflect the patient subtype repertoire. T cells derived from terminally engrafted spleens from the cord blood model recapitulate the T-cell subtype characteristics of CLL cells. (A) Representative immunohistological micrographs depicting engrafted human T-cell subtype marker expression. Images were captured by the Leica DMLB microscope with a Leica DFC320 camera (Milton Keynes, Buckinghamshire, UK) at 10× magnification prior to article production. (B) FACS analysis quantification and comparison of T-cell subsets in xenograft-derived splenic human cells CD8+, CD4+ and CD4+CD25+ (9 CLL, 20 mice) and CD4+CD25+FoxP3+ (5 CLL, 5 mice) and in patient samples (input) CD8+, CD4+ (11 CLL), CD4+CD25+ (10 CLL) and CD4+CD25+FoxP3+ cells (9 CLL). (C) Engraftment kinetics of the various patient-derived T-cell subsets were followed by analysis of sequentially sacrificed animals. Mice with CD14+ monocyte support were injected with PBMCs from one of three CLL patients (n=8 mice/CLL). A single animal from each cohort was sacrificed bi-weekly for 20 weeks and splenic cell composition analysed by FACS. Terminal engraftment had not been attained by this time-point. (D) Representative immunohistological micrographs illustrating the differing splenic distribution and contact between engrafted human CD19+ CLL cells (red) and either CD4+ or CD8+ T cells derived from indolent or progressive CLLs. Images were captured by the Nikon Eclipse E400 microscope with a Nikon DS-Fil camera linked to Nikon Digital Sight Capture (Kingston upon Thames, Surrey, UK) at 10× magnification prior to article production. Subtype proportions were compared using a two-tailed t-test (B), one-way ANOVA with Dunnett's post-test versus Input or two-way ANOVA with Bonferroni post-test versus Week 2 (C); *P≤0.05 (versus Input). Scale bars: 50 µm.
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DMM021147F3: Engrafted T cells reflect the patient subtype repertoire. T cells derived from terminally engrafted spleens from the cord blood model recapitulate the T-cell subtype characteristics of CLL cells. (A) Representative immunohistological micrographs depicting engrafted human T-cell subtype marker expression. Images were captured by the Leica DMLB microscope with a Leica DFC320 camera (Milton Keynes, Buckinghamshire, UK) at 10× magnification prior to article production. (B) FACS analysis quantification and comparison of T-cell subsets in xenograft-derived splenic human cells CD8+, CD4+ and CD4+CD25+ (9 CLL, 20 mice) and CD4+CD25+FoxP3+ (5 CLL, 5 mice) and in patient samples (input) CD8+, CD4+ (11 CLL), CD4+CD25+ (10 CLL) and CD4+CD25+FoxP3+ cells (9 CLL). (C) Engraftment kinetics of the various patient-derived T-cell subsets were followed by analysis of sequentially sacrificed animals. Mice with CD14+ monocyte support were injected with PBMCs from one of three CLL patients (n=8 mice/CLL). A single animal from each cohort was sacrificed bi-weekly for 20 weeks and splenic cell composition analysed by FACS. Terminal engraftment had not been attained by this time-point. (D) Representative immunohistological micrographs illustrating the differing splenic distribution and contact between engrafted human CD19+ CLL cells (red) and either CD4+ or CD8+ T cells derived from indolent or progressive CLLs. Images were captured by the Nikon Eclipse E400 microscope with a Nikon DS-Fil camera linked to Nikon Digital Sight Capture (Kingston upon Thames, Surrey, UK) at 10× magnification prior to article production. Subtype proportions were compared using a two-tailed t-test (B), one-way ANOVA with Dunnett's post-test versus Input or two-way ANOVA with Bonferroni post-test versus Week 2 (C); *P≤0.05 (versus Input). Scale bars: 50 µm.

Mentions: In the cord blood model, terminally engrafted T cells were predominantly of CD4+ subtype, regardless of the biological properties of the CLL and the length of CLL engraftment. The majority of T-cell subsets observed in patients could be detected in CLL xenografts in similar proportions, except for significantly (P≤0.05) elevated levels of T-regulatory cells (CD4+CD25+FoxP3+), typically associated with CLL progression (Jadidi-Niaragh et al., 2013) (Fig. 3A,B). Ratios of CD4 to CD8 were within the normal range for CLL (Nunes et al., 2012) and insignificantly altered from that of the patient PBMCs, thus remained characteristic of patient disease status (Fig. S5). The slight discrepancies between patient PBMCs and xenograft spleens were in accordance with observations in the NSG models suggesting that the CD4:CD8 ratio differed between murine peripheral blood and spleen (Bagnara et al., 2011). Thus, irrespective of the T-cell origin (patient-derived, cord blood-derived or a mixture) in the cord blood model (Fig. S3), the patient T-cell subset proportions were retained (Fig. 3B and Fig. S5).Fig. 3.


T-cell number and subtype influence the disease course of primary chronic lymphocytic leukaemia xenografts in alymphoid mice.

Oldreive CE, Skowronska A, Davies NJ, Parry H, Agathanggelou A, Krysov S, Packham G, Rudzki Z, Cronin L, Vrzalikova K, Murray P, Odintsova E, Pratt G, Taylor AM, Moss P, Stankovic T - Dis Model Mech (2015)

Engrafted T cells reflect the patient subtype repertoire. T cells derived from terminally engrafted spleens from the cord blood model recapitulate the T-cell subtype characteristics of CLL cells. (A) Representative immunohistological micrographs depicting engrafted human T-cell subtype marker expression. Images were captured by the Leica DMLB microscope with a Leica DFC320 camera (Milton Keynes, Buckinghamshire, UK) at 10× magnification prior to article production. (B) FACS analysis quantification and comparison of T-cell subsets in xenograft-derived splenic human cells CD8+, CD4+ and CD4+CD25+ (9 CLL, 20 mice) and CD4+CD25+FoxP3+ (5 CLL, 5 mice) and in patient samples (input) CD8+, CD4+ (11 CLL), CD4+CD25+ (10 CLL) and CD4+CD25+FoxP3+ cells (9 CLL). (C) Engraftment kinetics of the various patient-derived T-cell subsets were followed by analysis of sequentially sacrificed animals. Mice with CD14+ monocyte support were injected with PBMCs from one of three CLL patients (n=8 mice/CLL). A single animal from each cohort was sacrificed bi-weekly for 20 weeks and splenic cell composition analysed by FACS. Terminal engraftment had not been attained by this time-point. (D) Representative immunohistological micrographs illustrating the differing splenic distribution and contact between engrafted human CD19+ CLL cells (red) and either CD4+ or CD8+ T cells derived from indolent or progressive CLLs. Images were captured by the Nikon Eclipse E400 microscope with a Nikon DS-Fil camera linked to Nikon Digital Sight Capture (Kingston upon Thames, Surrey, UK) at 10× magnification prior to article production. Subtype proportions were compared using a two-tailed t-test (B), one-way ANOVA with Dunnett's post-test versus Input or two-way ANOVA with Bonferroni post-test versus Week 2 (C); *P≤0.05 (versus Input). Scale bars: 50 µm.
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Related In: Results  -  Collection

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DMM021147F3: Engrafted T cells reflect the patient subtype repertoire. T cells derived from terminally engrafted spleens from the cord blood model recapitulate the T-cell subtype characteristics of CLL cells. (A) Representative immunohistological micrographs depicting engrafted human T-cell subtype marker expression. Images were captured by the Leica DMLB microscope with a Leica DFC320 camera (Milton Keynes, Buckinghamshire, UK) at 10× magnification prior to article production. (B) FACS analysis quantification and comparison of T-cell subsets in xenograft-derived splenic human cells CD8+, CD4+ and CD4+CD25+ (9 CLL, 20 mice) and CD4+CD25+FoxP3+ (5 CLL, 5 mice) and in patient samples (input) CD8+, CD4+ (11 CLL), CD4+CD25+ (10 CLL) and CD4+CD25+FoxP3+ cells (9 CLL). (C) Engraftment kinetics of the various patient-derived T-cell subsets were followed by analysis of sequentially sacrificed animals. Mice with CD14+ monocyte support were injected with PBMCs from one of three CLL patients (n=8 mice/CLL). A single animal from each cohort was sacrificed bi-weekly for 20 weeks and splenic cell composition analysed by FACS. Terminal engraftment had not been attained by this time-point. (D) Representative immunohistological micrographs illustrating the differing splenic distribution and contact between engrafted human CD19+ CLL cells (red) and either CD4+ or CD8+ T cells derived from indolent or progressive CLLs. Images were captured by the Nikon Eclipse E400 microscope with a Nikon DS-Fil camera linked to Nikon Digital Sight Capture (Kingston upon Thames, Surrey, UK) at 10× magnification prior to article production. Subtype proportions were compared using a two-tailed t-test (B), one-way ANOVA with Dunnett's post-test versus Input or two-way ANOVA with Bonferroni post-test versus Week 2 (C); *P≤0.05 (versus Input). Scale bars: 50 µm.
Mentions: In the cord blood model, terminally engrafted T cells were predominantly of CD4+ subtype, regardless of the biological properties of the CLL and the length of CLL engraftment. The majority of T-cell subsets observed in patients could be detected in CLL xenografts in similar proportions, except for significantly (P≤0.05) elevated levels of T-regulatory cells (CD4+CD25+FoxP3+), typically associated with CLL progression (Jadidi-Niaragh et al., 2013) (Fig. 3A,B). Ratios of CD4 to CD8 were within the normal range for CLL (Nunes et al., 2012) and insignificantly altered from that of the patient PBMCs, thus remained characteristic of patient disease status (Fig. S5). The slight discrepancies between patient PBMCs and xenograft spleens were in accordance with observations in the NSG models suggesting that the CD4:CD8 ratio differed between murine peripheral blood and spleen (Bagnara et al., 2011). Thus, irrespective of the T-cell origin (patient-derived, cord blood-derived or a mixture) in the cord blood model (Fig. S3), the patient T-cell subset proportions were retained (Fig. 3B and Fig. S5).Fig. 3.

Bottom Line: Chronic lymphocytic leukaemia (CLL) cells require microenvironmental support for their proliferation.This can be recapitulated in highly immunocompromised hosts in the presence of T cells and other supporting cells.Thus, a greater understanding of the interaction between CLL and T cells could improve their utility.

View Article: PubMed Central - PubMed

Affiliation: School of Cancer Sciences, Department of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, UK.

No MeSH data available.


Related in: MedlinePlus