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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 delaying the time of initial administration of the blocking mAb DATK32 (anti-α4β7 integrin) on the recovery of MCp in the small intestine of BALB/c mice. The MCp concentrations were determined 7 d after sublethal irradiation and BM reconstitution and are expressed as the percent inhibition of MCp concentrations in the intestine relative to the mice treated with the isotype-matched rat anti–mouse IgD mAb. The control mice had an average MCp concentration of 632 ± 206 MCp/106 MNCs (mean ± SEM, n = 6). Experimental values are the mean ± SEM of four (day 0 and day 2) or two (day 4 and day 6) experiments.
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fig6: Effect of delaying the time of initial administration of the blocking mAb DATK32 (anti-α4β7 integrin) on the recovery of MCp in the small intestine of BALB/c mice. The MCp concentrations were determined 7 d after sublethal irradiation and BM reconstitution and are expressed as the percent inhibition of MCp concentrations in the intestine relative to the mice treated with the isotype-matched rat anti–mouse IgD mAb. The control mice had an average MCp concentration of 632 ± 206 MCp/106 MNCs (mean ± SEM, n = 6). Experimental values are the mean ± SEM of four (day 0 and day 2) or two (day 4 and day 6) experiments.

Mentions: Because the recovery of MCp in recipient BM preceded recovery in the intestine, the effectiveness of delaying the introduction of the blocking mAb on the recovery of intestinal MCp was determined. The blocking mAb to the combinatorial epitope of α4β7 integrin (DATK32) was fully effective when the first dose was delayed to day 2 or even day 4 and was partially effective with a single dose on day 6 as compared with the initial administration on day 0 when MCp concentrations were assessed on day 7 (Fig. 6) . Comparable inhibition also was obtained in one experiment in which intestinal MCp were quantitated on day 11 after sublethal irradiation and BM reconstitution and the administration of anti-α4β7 integrin mAb was initiated on day 2 or 6. The administration of DATK32 beginning on day 2 gave 92% inhibition, and on day 6 gave 76% inhibition relative to the effect of an irrelevant isotype-matched mAb given beginning on day 2. As the administration of blocking mAb could be delayed for several days, the reconstituting syngeneic cells required conditioning in the recipient BM for lineage development before distribution of MCp to the intestine.


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 delaying the time of initial administration of the blocking mAb DATK32 (anti-α4β7 integrin) on the recovery of MCp in the small intestine of BALB/c mice. The MCp concentrations were determined 7 d after sublethal irradiation and BM reconstitution and are expressed as the percent inhibition of MCp concentrations in the intestine relative to the mice treated with the isotype-matched rat anti–mouse IgD mAb. The control mice had an average MCp concentration of 632 ± 206 MCp/106 MNCs (mean ± SEM, n = 6). Experimental values are the mean ± SEM of four (day 0 and day 2) or two (day 4 and day 6) experiments.
© Copyright Policy
Related In: Results  -  Collection

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

fig6: Effect of delaying the time of initial administration of the blocking mAb DATK32 (anti-α4β7 integrin) on the recovery of MCp in the small intestine of BALB/c mice. The MCp concentrations were determined 7 d after sublethal irradiation and BM reconstitution and are expressed as the percent inhibition of MCp concentrations in the intestine relative to the mice treated with the isotype-matched rat anti–mouse IgD mAb. The control mice had an average MCp concentration of 632 ± 206 MCp/106 MNCs (mean ± SEM, n = 6). Experimental values are the mean ± SEM of four (day 0 and day 2) or two (day 4 and day 6) experiments.
Mentions: Because the recovery of MCp in recipient BM preceded recovery in the intestine, the effectiveness of delaying the introduction of the blocking mAb on the recovery of intestinal MCp was determined. The blocking mAb to the combinatorial epitope of α4β7 integrin (DATK32) was fully effective when the first dose was delayed to day 2 or even day 4 and was partially effective with a single dose on day 6 as compared with the initial administration on day 0 when MCp concentrations were assessed on day 7 (Fig. 6) . Comparable inhibition also was obtained in one experiment in which intestinal MCp were quantitated on day 11 after sublethal irradiation and BM reconstitution and the administration of anti-α4β7 integrin mAb was initiated on day 2 or 6. The administration of DATK32 beginning on day 2 gave 92% inhibition, and on day 6 gave 76% inhibition relative to the effect of an irrelevant isotype-matched mAb given beginning on day 2. As the administration of blocking mAb could be delayed for several days, the reconstituting syngeneic cells required conditioning in the recipient BM for lineage development before distribution of MCp to the intestine.

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