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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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Comparison of the inhibition by mAb to α4β7, β7, αE, or β1 integrins of the recovery of MCp in the small intestine of BALB/c mice. Animals received 30 μg of the indicated mAb, DATK32, FIB27, M290, or 9EG7, directed against α4β7, β7, αE, or β1 integrins, respectively, starting 0 or 2 d after sublethal irradiation and BM reconstitution. Values represent the mean ± SEM percent inhibition relative to control animals treated in parallel. MCp concentrations were analyzed 7 or 8 d after sublethal irradiation and BM reconstitution. Means are from seven (DATK32), three (FIB27, M290), or four (9EG7) experiments. The mean MCp concentration for the control mice was 622 ± 65 MCp/106 MNCs (mean ± SEM). Asterisks indicate statistically significant inhibition relative to mice injected with anti-β1 integrin mAb (P < 0.03).
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fig7: Comparison of the inhibition by mAb to α4β7, β7, αE, or β1 integrins of the recovery of MCp in the small intestine of BALB/c mice. Animals received 30 μg of the indicated mAb, DATK32, FIB27, M290, or 9EG7, directed against α4β7, β7, αE, or β1 integrins, respectively, starting 0 or 2 d after sublethal irradiation and BM reconstitution. Values represent the mean ± SEM percent inhibition relative to control animals treated in parallel. MCp concentrations were analyzed 7 or 8 d after sublethal irradiation and BM reconstitution. Means are from seven (DATK32), three (FIB27, M290), or four (9EG7) experiments. The mean MCp concentration for the control mice was 622 ± 65 MCp/106 MNCs (mean ± SEM). Asterisks indicate statistically significant inhibition relative to mice injected with anti-β1 integrin mAb (P < 0.03).

Mentions: To evaluate the integrin specificity of MCp recovery in the intestine after sublethal irradiation and BM reconstitution, we compared the inhibition obtained with anti-β7 integrin (FIB27, rat IgG2a), anti-αE integrin (M290, rat IgG2a), or anti-β1 integrin (9EG7, rat IgG2a) mAb to that obtained with the isotype matched anti-α4β7 integrin (DATK32) mAb. The MCp concentration was evaluated 7 or 8 d after sublethal irradiation and BM reconstitution (Fig. 7) . The anti-α4β7 integrin mAb DATK32 blocked MCp reconstitution in the intestine by 74 ± 5% (mean ± SEM, n = 7), and the anti-β7 integrin mAb blocked reconstitution by 53 ± 14% (n = 3). In contrast, neither of the isotype-matched mAbs reacting with αE (CD103) or β1 (CD29) integrins had any significant effect on MCp recovery in the intestine (11 ± 16% inhibition, n = 3, and 5 ± 8% inhibition, n = 4, respectively). Similar results were also obtained with the hamster anti–mouse β1 integrin mAb, Ha2/5 (hamster IgM, mean % inhibition ± SEM = −7 ± 19%, n = 4). The inhibition obtained with DATK32 was statistically significant compared with that obtained with M290 and 9EG7 (P ≤ 0.001), whereas the inhibition obtained with FIB27 was significantly different from that obtained with 9EG7 (P = 0.026), as analyzed by the Student's t test. As MAdCAM-1 is a high endothelial cell ligand for α4β7 integrin in the small intestine, we also examined the blocking of intestinal MCp recovery by anti–MAdCAM-1 mAb (MECA-367). After sublethal irradiation and BM reconstitution, administration of anti–MAdCAM-1 mAb beginning on day 2, with analysis on day 7, revealed a 45 ± 5% suppression (mean ± SEM, n = 3) compared with mice receiving an isotype-matched control mAb.


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)

Comparison of the inhibition by mAb to α4β7, β7, αE, or β1 integrins of the recovery of MCp in the small intestine of BALB/c mice. Animals received 30 μg of the indicated mAb, DATK32, FIB27, M290, or 9EG7, directed against α4β7, β7, αE, or β1 integrins, respectively, starting 0 or 2 d after sublethal irradiation and BM reconstitution. Values represent the mean ± SEM percent inhibition relative to control animals treated in parallel. MCp concentrations were analyzed 7 or 8 d after sublethal irradiation and BM reconstitution. Means are from seven (DATK32), three (FIB27, M290), or four (9EG7) experiments. The mean MCp concentration for the control mice was 622 ± 65 MCp/106 MNCs (mean ± SEM). Asterisks indicate statistically significant inhibition relative to mice injected with anti-β1 integrin mAb (P < 0.03).
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Related In: Results  -  Collection

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fig7: Comparison of the inhibition by mAb to α4β7, β7, αE, or β1 integrins of the recovery of MCp in the small intestine of BALB/c mice. Animals received 30 μg of the indicated mAb, DATK32, FIB27, M290, or 9EG7, directed against α4β7, β7, αE, or β1 integrins, respectively, starting 0 or 2 d after sublethal irradiation and BM reconstitution. Values represent the mean ± SEM percent inhibition relative to control animals treated in parallel. MCp concentrations were analyzed 7 or 8 d after sublethal irradiation and BM reconstitution. Means are from seven (DATK32), three (FIB27, M290), or four (9EG7) experiments. The mean MCp concentration for the control mice was 622 ± 65 MCp/106 MNCs (mean ± SEM). Asterisks indicate statistically significant inhibition relative to mice injected with anti-β1 integrin mAb (P < 0.03).
Mentions: To evaluate the integrin specificity of MCp recovery in the intestine after sublethal irradiation and BM reconstitution, we compared the inhibition obtained with anti-β7 integrin (FIB27, rat IgG2a), anti-αE integrin (M290, rat IgG2a), or anti-β1 integrin (9EG7, rat IgG2a) mAb to that obtained with the isotype matched anti-α4β7 integrin (DATK32) mAb. The MCp concentration was evaluated 7 or 8 d after sublethal irradiation and BM reconstitution (Fig. 7) . The anti-α4β7 integrin mAb DATK32 blocked MCp reconstitution in the intestine by 74 ± 5% (mean ± SEM, n = 7), and the anti-β7 integrin mAb blocked reconstitution by 53 ± 14% (n = 3). In contrast, neither of the isotype-matched mAbs reacting with αE (CD103) or β1 (CD29) integrins had any significant effect on MCp recovery in the intestine (11 ± 16% inhibition, n = 3, and 5 ± 8% inhibition, n = 4, respectively). Similar results were also obtained with the hamster anti–mouse β1 integrin mAb, Ha2/5 (hamster IgM, mean % inhibition ± SEM = −7 ± 19%, n = 4). The inhibition obtained with DATK32 was statistically significant compared with that obtained with M290 and 9EG7 (P ≤ 0.001), whereas the inhibition obtained with FIB27 was significantly different from that obtained with 9EG7 (P = 0.026), as analyzed by the Student's t test. As MAdCAM-1 is a high endothelial cell ligand for α4β7 integrin in the small intestine, we also examined the blocking of intestinal MCp recovery by anti–MAdCAM-1 mAb (MECA-367). After sublethal irradiation and BM reconstitution, administration of anti–MAdCAM-1 mAb beginning on day 2, with analysis on day 7, revealed a 45 ± 5% suppression (mean ± SEM, n = 3) compared with mice receiving an isotype-matched control mAb.

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