Xenogeneic Extracellular Matrix Grafts Elicit a Th2-Restricted Immune Response1

Allman, Amy J; McPherson, Timothy; Badylak, Stephen F.; Merrill, Lisa C.; Kallakury, Bhaskar; Sheehan, Christine E.; Raeder, Roberta; Metzger, Dennis W.

doi:10.1097/00007890-200106150-00024

Cited by 354 publications

(333 citation statements)

References 25 publications

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“…Donor-derived MHC class I, which immunolocalized preferentially to donor endothelial cells, became undetectable during decellularization, but was again measurable in the host blood vessels following implantation (host-derived MHC class I), in agreement with previous studies that have demonstrated evasion of rejection when the donor is vascularized by host blood vessels (48,49). As well as a shift toward an M2-like phenotype with decellularization, we have also observed a shift away from a TH1 (as in classical acute rejection, for example) toward a TH2-like phenotype (generally associated with transplant acceptance), in agreement with previous studies (32,50,51).…”

Section: -47)supporting

confidence: 92%

Immunomodulatory effect of a decellularized skeletal muscle scaffold in a discordant xenotransplantation model

Fishman

Lowdell

Urbani³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

184

137

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Decellularized (acellular) scaffolds, composed of natural extracellular matrix, form the basis of an emerging generation of tissueengineered organ and tissue replacements capable of transforming healthcare. Prime requirements for allogeneic, or xenogeneic, decellularized scaffolds are biocompatibility and absence of rejection. The humoral immune response to decellularized scaffolds has been well documented, but there is a lack of data on the cellmediated immune response toward them in vitro and in vivo. Skeletal muscle scaffolds were decellularized, characterized in vitro, and xenotransplanted. The cellular immune response toward scaffolds was evaluated by immunohistochemistry and quantified stereologically. T-cell proliferation and cytokines, as assessed by flow cytometry using carboxy-fluorescein diacetate succinimidyl ester dye and cytometric bead array, formed an in vitro surrogate marker and correlate of the in vivo host immune response toward the scaffold. Decellularized scaffolds were free of major histocompatibility complex class I and II antigens and were found to exert anti-inflammatory and immunosuppressive effects, as evidenced by delayed biodegradation time in vivo; reduced sensitized T-cell proliferative activity in vitro; reduced IL-2, IFN-γ, and raised IL-10 levels in cell-culture supernatants; polarization of the macrophage response in vivo toward an M2 phenotype; and improved survival of donor-derived xenogeneic cells at 2 and 4 wk in vivo. Decellularized scaffolds polarize host responses away from a classical TH1-proinflammatory profile and appear to down-regulate T-cell xeno responses and TH1 effector function by inducing a state of peripheral T-cell hyporesponsiveness. These results have substantial implications for the future clinical application of tissue-engineered therapies.

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Section: -47)supporting

confidence: 92%

Immunomodulatory effect of a decellularized skeletal muscle scaffold in a discordant xenotransplantation model

Fishman

Lowdell

Urbani³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

184

137

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“…S1) and systemically (50), promote a local microenvironmental niche that facilitates stem cell recruitment and/or maintenance (51-53). An independent contributing factor to the host response is the effect of ECM scaffolds on tissue macrophages (33,(54)(55)(56) and T cells (57). Macrophages are critical determinants of the overall regenerative response in vivo (56).…”

Section: Discussionmentioning

confidence: 99%

Epimorphic regeneration approach to tissue replacement in adult mammals

Agrawal

Johnson²,

Reing³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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143

134

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Urodeles and fetal mammals are capable of impressive epimorphic regeneration in a variety of tissues, whereas the typical default response to injury in adult mammals consists of inflammation and scar tissue formation. One component of epimorphic regeneration is the recruitment of resident progenitor and stem cells to a site of injury. Bioactive molecules resulting from degradation of extracellular matrix (ECM) have been shown to recruit a variety of progenitor and stem cells in vitro in adult mammals. The ability to recruit multipotential cells to the site of injury by in vivo administration of chemotactic ECM degradation products in a mammalian model of digit amputation was investigated in the present study. Adult, 6- to 8-week-old C57/BL6 mice were subjected to midsecond phalanx amputation of the third digit of the right hind foot and either treated with chemotactic ECM degradation products or left untreated. At 14 days after amputation, mice treated with ECM degradation products showed an accumulation of heterogeneous cells that expressed markers of multipotency, including Sox2, Sca1, and Rex1 (Zfp42). Cells isolated from the site of amputation were capable of differentiation along neuroectodermal and mesodermal lineages, whereas cells isolated from control mice were capable of differentiation along only mesodermal lineages. The present findings demonstrate the recruitment of endogenous stem cells to a site of injury, and/or their generation/proliferation therein, in response to ECM degradation products.

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“…are relatively well conserved across mammalian species and, therefore, do not evoke adverse immune reaction. 25,26 However, a number of recent studies have shown that cellular components may remain after decellularization in a number of ECM materials, even those that have received approval for clinical use. 27 Further studies have suggested that inefficient removal of cellular contents such as DNA and the a-gal epitope during decellularization may be responsible for inflammation and poor outcomes after implantation.…”

mentioning

confidence: 99%

Comparison of Three Methods for the Derivation of a Biologic Scaffold Composed of Adipose Tissue Extracellular Matrix

Brown

Freund

Han

et al. 2011

Tissue Engineering Part C: Methods

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194

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Xenogeneic Extracellular Matrix Grafts Elicit a Th2-Restricted Immune Response1

Abstract: Porcine extracellular matrix elicits an immune response that is predominately Th2-like, consistent with a remodeling reaction rather than rejection.

Cited by 354 publications

References 25 publications

Immunomodulatory effect of a decellularized skeletal muscle scaffold in a discordant xenotransplantation model

Immunomodulatory effect of a decellularized skeletal muscle scaffold in a discordant xenotransplantation model

Epimorphic regeneration approach to tissue replacement in adult mammals

Comparison of Three Methods for the Derivation of a Biologic Scaffold Composed of Adipose Tissue Extracellular Matrix

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