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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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Inhibition by mAb to α4β7 integrin of the recovery of MCp in the small intestine of BALB/c mice is accompanied by increased MCp in the lung. Animals received 30 μg of the mAb, DATK32, directed against the α4β7 integrin, or a control injection of HBSS or isotype matched rat mAb, starting 2 d after sublethal irradiation and BM reconstitution. Values represent the mean ± SEM (n = 4) of the MCp concentration in the indicated tissues expressed as a percentage of the value obtained from control animals treated in parallel. MCp concentrations were analyzed 7 d after sublethal irradiation and BM reconstitution. The MCp concentrations for the control mice were 1,068 ± 390 and 252 ± 51 MCp/106 MNCs (mean ± SEM) for the intestine and lung, respectively.
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fig8: Inhibition by mAb to α4β7 integrin of the recovery of MCp in the small intestine of BALB/c mice is accompanied by increased MCp in the lung. Animals received 30 μg of the mAb, DATK32, directed against the α4β7 integrin, or a control injection of HBSS or isotype matched rat mAb, starting 2 d after sublethal irradiation and BM reconstitution. Values represent the mean ± SEM (n = 4) of the MCp concentration in the indicated tissues expressed as a percentage of the value obtained from control animals treated in parallel. MCp concentrations were analyzed 7 d after sublethal irradiation and BM reconstitution. The MCp concentrations for the control mice were 1,068 ± 390 and 252 ± 51 MCp/106 MNCs (mean ± SEM) for the intestine and lung, respectively.

Mentions: The evidence that anti-α4β7 or anti-α4 integrin, in contradistinction to the findings for αE or β1 integrins, blocked reconstitution of MCp in the small intestine led to a parallel assessment of the role of α4β7 integrin for homing of MCp to the lung. Whereas mice receiving anti-α4β7 integrin restored only 30.9 ± 9.6% (mean ± SEM) of their MCp in the small intestine, the lung concentration of MCp was increased to 275.1 ± 57.5% relative to isotype-matched control mAb injected mice in four separate experiments assayed on day 7 after sublethal irradiation and BM reconstitution (Fig. 8) .


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)

Inhibition by mAb to α4β7 integrin of the recovery of MCp in the small intestine of BALB/c mice is accompanied by increased MCp in the lung. Animals received 30 μg of the mAb, DATK32, directed against the α4β7 integrin, or a control injection of HBSS or isotype matched rat mAb, starting 2 d after sublethal irradiation and BM reconstitution. Values represent the mean ± SEM (n = 4) of the MCp concentration in the indicated tissues expressed as a percentage of the value obtained from control animals treated in parallel. MCp concentrations were analyzed 7 d after sublethal irradiation and BM reconstitution. The MCp concentrations for the control mice were 1,068 ± 390 and 252 ± 51 MCp/106 MNCs (mean ± SEM) for the intestine and lung, respectively.
© Copyright Policy
Related In: Results  -  Collection

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

fig8: Inhibition by mAb to α4β7 integrin of the recovery of MCp in the small intestine of BALB/c mice is accompanied by increased MCp in the lung. Animals received 30 μg of the mAb, DATK32, directed against the α4β7 integrin, or a control injection of HBSS or isotype matched rat mAb, starting 2 d after sublethal irradiation and BM reconstitution. Values represent the mean ± SEM (n = 4) of the MCp concentration in the indicated tissues expressed as a percentage of the value obtained from control animals treated in parallel. MCp concentrations were analyzed 7 d after sublethal irradiation and BM reconstitution. The MCp concentrations for the control mice were 1,068 ± 390 and 252 ± 51 MCp/106 MNCs (mean ± SEM) for the intestine and lung, respectively.
Mentions: The evidence that anti-α4β7 or anti-α4 integrin, in contradistinction to the findings for αE or β1 integrins, blocked reconstitution of MCp in the small intestine led to a parallel assessment of the role of α4β7 integrin for homing of MCp to the lung. Whereas mice receiving anti-α4β7 integrin restored only 30.9 ± 9.6% (mean ± SEM) of their MCp in the small intestine, the lung concentration of MCp was increased to 275.1 ± 57.5% relative to isotype-matched control mAb injected mice in four separate experiments assayed on day 7 after sublethal irradiation and BM reconstitution (Fig. 8) .

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