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Intestinal mast cell progenitors require CD49dbeta7 (alpha4beta7 integrin) for tissue-specific homing.

Gurish MF, Tao H, Abonia JP, Arya A, Friend DS, Parker CM, Austen KF - J. Exp. Med. (2001)

Bottom Line: A single lineage of bone marrow (BM)-derived progenitors emigrates from the circulation and matures into phenotypically distinct MCs in different tissues.Therefore, it is the alpha4beta7 integrin and not the alphaEbeta7 integrin that is critical, and lymphocytes and natural killer cells play no role in directing MCp migration under basal conditions.The blocking mAbs could be administered as late as 4 d after BM reconstitution with optimal inhibition, implying that the MCp must arise first in the BM, circulate in the vasculature, and then translocate into the intestine.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. mgurish@rics.bwh.harvard.edu

ABSTRACT
Mast cells (MCs) are centrally important in allergic inflammation of the airways, as well as in the intestinal immune response to helminth infection. A single lineage of bone marrow (BM)-derived progenitors emigrates from the circulation and matures into phenotypically distinct MCs in different tissues. Because the mechanisms of MC progenitor (MCp) homing to peripheral tissues have not been evaluated, we used limiting dilution analysis to measure the concentration of MCp in various tissues of mice deficient for candidate homing molecules. MCp were almost completely absent in the small intestine but were present in the lung, spleen, BM, and large intestine of beta7 integrin-deficient mice (on the C57BL/6 background), indicating that a beta7 integrin is critical for homing of these cells to the small intestine. MCp concentrations were not altered in the tissues of mice deficient in the alphaE integrin (CD103), the beta2 integrin (CD18), or the recombination activating gene (RAG)-2 gene either alone or in combination with the interleukin (IL)-receptor common gamma chain. Therefore, it is the alpha4beta7 integrin and not the alphaEbeta7 integrin that is critical, and lymphocytes and natural killer cells play no role in directing MCp migration under basal conditions. When MCp in BALB/c mice were eliminated with sublethal doses of gamma-radiation and then reconstituted with syngeneic BM, the administration of anti-alpha4beta7 integrin, anti-alpha4 integrin, anti-beta7 integrin, or anti-MAdCAM-1 monoclonal antibodies (mAbs) blocked the recovery of MCp in the small intestine. The blocking mAbs could be administered as late as 4 d after BM reconstitution with optimal inhibition, implying that the MCp must arise first in the BM, circulate in the vasculature, and then translocate into the intestine. Inasmuch as MCp are preserved in the lungs of beta7 integrin-deficient and anti-alpha4beta7 integrin-treated mice but not in the small intestine, alpha4beta7 integrin is critical for tissue specific extravasation for localization of MCp in the small intestine, but not the lungs.

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Effect of the blocking anti-integrin mAb, PS/2 (anti-α4, rat IgG2b, open circles) and DATK32 (anti-α4β7, rat IgG2a, filled circles), on the recovery of MCp in the small intestine of BALB/c mice. MCp concentrations were determined 9 d after sublethal irradiation and BM reconstitution and are expressed as the percent inhibition of MCp concentrations in the intestine relative to mice treated with a control mAb (rat anti–mouse IgD, IgG2a) or HBSS. mAb was diluted in HBSS and administered intraperitoneally every other day starting 4 h after BM reconstitution. The results are the average inhibition for two or three experiments with the following n values: For PS/2, 100 μg, n = 2; 30 μg, n = 3, 10 μg and 1 μg, n = 1; for DATK32, 30 μg, n = 3, for 10 μg, 1 μg, and 0.1 μg, n = 1. The average concentration of intestinal MCp for mice given the control mAb or HBSS was 903 ± 311 MCp/106 MNCs (mean ± SEM, n = 5).
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fig5: Effect of the blocking anti-integrin mAb, PS/2 (anti-α4, rat IgG2b, open circles) and DATK32 (anti-α4β7, rat IgG2a, filled circles), on the recovery of MCp in the small intestine of BALB/c mice. MCp concentrations were determined 9 d after sublethal irradiation and BM reconstitution and are expressed as the percent inhibition of MCp concentrations in the intestine relative to mice treated with a control mAb (rat anti–mouse IgD, IgG2a) or HBSS. mAb was diluted in HBSS and administered intraperitoneally every other day starting 4 h after BM reconstitution. The results are the average inhibition for two or three experiments with the following n values: For PS/2, 100 μg, n = 2; 30 μg, n = 3, 10 μg and 1 μg, n = 1; for DATK32, 30 μg, n = 3, for 10 μg, 1 μg, and 0.1 μg, n = 1. The average concentration of intestinal MCp for mice given the control mAb or HBSS was 903 ± 311 MCp/106 MNCs (mean ± SEM, n = 5).

Mentions: The high affinity mAb PS/2 (rat IgG2b) recognizes and blocks the binding function of both α4β1 and α4β7 integrins, whereas the mAb DATK32 (rat IgG2a) recognizes a combinatorial determinate and blocks binding only by the α4β7 integrin (32, 37). The dose-dependent effect of administering anti-α4 (PS/2) and anti-α4β7 (DATK32) integrin mAbs on the recovery of MCp in the intestine was determined with the sublethal irradiation and BM reconstitution procedure and compared with the effect of a control mAb, rat anti–mouse IgD (rat IgG2a). All doses greater than 1 μg (given intraperitoneally every other day) of either the anti-α4 or the anti-α4β7 integrin mAb caused ∼70% inhibition of MCp reconstitution (Fig. 5) . As a dose of 30 μg of either mAb consistently gave ∼70% inhibition, this dose was chosen for subsequent experiments. No effect on BM MCp concentrations was observed in mice given either PS/2 or DATK32 (data not shown).


Intestinal mast cell progenitors require CD49dbeta7 (alpha4beta7 integrin) for tissue-specific homing.

Gurish MF, Tao H, Abonia JP, Arya A, Friend DS, Parker CM, Austen KF - J. Exp. Med. (2001)

Effect of the blocking anti-integrin mAb, PS/2 (anti-α4, rat IgG2b, open circles) and DATK32 (anti-α4β7, rat IgG2a, filled circles), on the recovery of MCp in the small intestine of BALB/c mice. MCp concentrations were determined 9 d after sublethal irradiation and BM reconstitution and are expressed as the percent inhibition of MCp concentrations in the intestine relative to mice treated with a control mAb (rat anti–mouse IgD, IgG2a) or HBSS. mAb was diluted in HBSS and administered intraperitoneally every other day starting 4 h after BM reconstitution. The results are the average inhibition for two or three experiments with the following n values: For PS/2, 100 μg, n = 2; 30 μg, n = 3, 10 μg and 1 μg, n = 1; for DATK32, 30 μg, n = 3, for 10 μg, 1 μg, and 0.1 μg, n = 1. The average concentration of intestinal MCp for mice given the control mAb or HBSS was 903 ± 311 MCp/106 MNCs (mean ± SEM, n = 5).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2195984&req=5

fig5: Effect of the blocking anti-integrin mAb, PS/2 (anti-α4, rat IgG2b, open circles) and DATK32 (anti-α4β7, rat IgG2a, filled circles), on the recovery of MCp in the small intestine of BALB/c mice. MCp concentrations were determined 9 d after sublethal irradiation and BM reconstitution and are expressed as the percent inhibition of MCp concentrations in the intestine relative to mice treated with a control mAb (rat anti–mouse IgD, IgG2a) or HBSS. mAb was diluted in HBSS and administered intraperitoneally every other day starting 4 h after BM reconstitution. The results are the average inhibition for two or three experiments with the following n values: For PS/2, 100 μg, n = 2; 30 μg, n = 3, 10 μg and 1 μg, n = 1; for DATK32, 30 μg, n = 3, for 10 μg, 1 μg, and 0.1 μg, n = 1. The average concentration of intestinal MCp for mice given the control mAb or HBSS was 903 ± 311 MCp/106 MNCs (mean ± SEM, n = 5).
Mentions: The high affinity mAb PS/2 (rat IgG2b) recognizes and blocks the binding function of both α4β1 and α4β7 integrins, whereas the mAb DATK32 (rat IgG2a) recognizes a combinatorial determinate and blocks binding only by the α4β7 integrin (32, 37). The dose-dependent effect of administering anti-α4 (PS/2) and anti-α4β7 (DATK32) integrin mAbs on the recovery of MCp in the intestine was determined with the sublethal irradiation and BM reconstitution procedure and compared with the effect of a control mAb, rat anti–mouse IgD (rat IgG2a). All doses greater than 1 μg (given intraperitoneally every other day) of either the anti-α4 or the anti-α4β7 integrin mAb caused ∼70% inhibition of MCp reconstitution (Fig. 5) . As a dose of 30 μg of either mAb consistently gave ∼70% inhibition, this dose was chosen for subsequent experiments. No effect on BM MCp concentrations was observed in mice given either PS/2 or DATK32 (data not shown).

Bottom Line: A single lineage of bone marrow (BM)-derived progenitors emigrates from the circulation and matures into phenotypically distinct MCs in different tissues.Therefore, it is the alpha4beta7 integrin and not the alphaEbeta7 integrin that is critical, and lymphocytes and natural killer cells play no role in directing MCp migration under basal conditions.The blocking mAbs could be administered as late as 4 d after BM reconstitution with optimal inhibition, implying that the MCp must arise first in the BM, circulate in the vasculature, and then translocate into the intestine.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. mgurish@rics.bwh.harvard.edu

ABSTRACT
Mast cells (MCs) are centrally important in allergic inflammation of the airways, as well as in the intestinal immune response to helminth infection. A single lineage of bone marrow (BM)-derived progenitors emigrates from the circulation and matures into phenotypically distinct MCs in different tissues. Because the mechanisms of MC progenitor (MCp) homing to peripheral tissues have not been evaluated, we used limiting dilution analysis to measure the concentration of MCp in various tissues of mice deficient for candidate homing molecules. MCp were almost completely absent in the small intestine but were present in the lung, spleen, BM, and large intestine of beta7 integrin-deficient mice (on the C57BL/6 background), indicating that a beta7 integrin is critical for homing of these cells to the small intestine. MCp concentrations were not altered in the tissues of mice deficient in the alphaE integrin (CD103), the beta2 integrin (CD18), or the recombination activating gene (RAG)-2 gene either alone or in combination with the interleukin (IL)-receptor common gamma chain. Therefore, it is the alpha4beta7 integrin and not the alphaEbeta7 integrin that is critical, and lymphocytes and natural killer cells play no role in directing MCp migration under basal conditions. When MCp in BALB/c mice were eliminated with sublethal doses of gamma-radiation and then reconstituted with syngeneic BM, the administration of anti-alpha4beta7 integrin, anti-alpha4 integrin, anti-beta7 integrin, or anti-MAdCAM-1 monoclonal antibodies (mAbs) blocked the recovery of MCp in the small intestine. The blocking mAbs could be administered as late as 4 d after BM reconstitution with optimal inhibition, implying that the MCp must arise first in the BM, circulate in the vasculature, and then translocate into the intestine. Inasmuch as MCp are preserved in the lungs of beta7 integrin-deficient and anti-alpha4beta7 integrin-treated mice but not in the small intestine, alpha4beta7 integrin is critical for tissue specific extravasation for localization of MCp in the small intestine, but not the lungs.

Show MeSH
Related in: MedlinePlus