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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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Recovery of MCp in the small intestine of BALB/c mice after sublethal irradiation with (filled circles) or without (open circles) BM reconstitution (BMR). Values for MCp concentrations without BM reconstitution are the mean ± 1/2 range of two experiments. Values for animals receiving BM reconstitution are the mean ± SEM of the following number of experiments: day 7, n = 12; day 8, n = 9; day 9, n = 6; day 11, n = 5; day 14, n = 4. MCp concentrations were determined with SCF plus IL-3. The shaded area represents the mean ± SEM concentration of MCp in normal BALB/c small intestine (from Fig. 1, SCF plus IL-3).
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fig4: Recovery of MCp in the small intestine of BALB/c mice after sublethal irradiation with (filled circles) or without (open circles) BM reconstitution (BMR). Values for MCp concentrations without BM reconstitution are the mean ± 1/2 range of two experiments. Values for animals receiving BM reconstitution are the mean ± SEM of the following number of experiments: day 7, n = 12; day 8, n = 9; day 9, n = 6; day 11, n = 5; day 14, n = 4. MCp concentrations were determined with SCF plus IL-3. The shaded area represents the mean ± SEM concentration of MCp in normal BALB/c small intestine (from Fig. 1, SCF plus IL-3).

Mentions: Kitamura and others have demonstrated that BM reconstitutes the MC populations in W/Wv MC-deficient mice and that BM MCp are very sensitive to gamma-irradiation (11, 15, 35, 36). Thus, we evaluated the loss and recovery of MCp in the BM, intestine, and lung of BALB/c mice exposed to sublethal irradiation, with and without reconstitution by administration of syngeneic BM cells. In the absence of BM reconstitution, the recovery of the MCp concentration in the small intestine is slow (Fig. 4) . With BM reconstitution, the recovery of intestinal MCp reaches 20% by day 7, 40% by day 9, and normal levels by day 11 (Fig. 4). The recovery of the MCp concentration in the BM of the reconstituted mice occurs even more rapidly, with normal levels obtained 4 d after irradiation, the earliest time point evaluated (data not shown, n = 3). The levels of MCp were ∼50% of normal in the lung 7 d after sublethal irradiation and BM reconstitution (data not shown, n = 2). The partial recovery of MCp concentrations in the intestine and lung 7–9 d after sublethal irradiation and BM reconstitution provided a reference against which the effect of administering blocking mAbs to various integrins could be quantitated.


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)

Recovery of MCp in the small intestine of BALB/c mice after sublethal irradiation with (filled circles) or without (open circles) BM reconstitution (BMR). Values for MCp concentrations without BM reconstitution are the mean ± 1/2 range of two experiments. Values for animals receiving BM reconstitution are the mean ± SEM of the following number of experiments: day 7, n = 12; day 8, n = 9; day 9, n = 6; day 11, n = 5; day 14, n = 4. MCp concentrations were determined with SCF plus IL-3. The shaded area represents the mean ± SEM concentration of MCp in normal BALB/c small intestine (from Fig. 1, SCF plus IL-3).
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Related In: Results  -  Collection

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fig4: Recovery of MCp in the small intestine of BALB/c mice after sublethal irradiation with (filled circles) or without (open circles) BM reconstitution (BMR). Values for MCp concentrations without BM reconstitution are the mean ± 1/2 range of two experiments. Values for animals receiving BM reconstitution are the mean ± SEM of the following number of experiments: day 7, n = 12; day 8, n = 9; day 9, n = 6; day 11, n = 5; day 14, n = 4. MCp concentrations were determined with SCF plus IL-3. The shaded area represents the mean ± SEM concentration of MCp in normal BALB/c small intestine (from Fig. 1, SCF plus IL-3).
Mentions: Kitamura and others have demonstrated that BM reconstitutes the MC populations in W/Wv MC-deficient mice and that BM MCp are very sensitive to gamma-irradiation (11, 15, 35, 36). Thus, we evaluated the loss and recovery of MCp in the BM, intestine, and lung of BALB/c mice exposed to sublethal irradiation, with and without reconstitution by administration of syngeneic BM cells. In the absence of BM reconstitution, the recovery of the MCp concentration in the small intestine is slow (Fig. 4) . With BM reconstitution, the recovery of intestinal MCp reaches 20% by day 7, 40% by day 9, and normal levels by day 11 (Fig. 4). The recovery of the MCp concentration in the BM of the reconstituted mice occurs even more rapidly, with normal levels obtained 4 d after irradiation, the earliest time point evaluated (data not shown, n = 3). The levels of MCp were ∼50% of normal in the lung 7 d after sublethal irradiation and BM reconstitution (data not shown, n = 2). The partial recovery of MCp concentrations in the intestine and lung 7–9 d after sublethal irradiation and BM reconstitution provided a reference against which the effect of administering blocking mAbs to various integrins could be quantitated.

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