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Cited by 388Xenotransplantation and immune responseTissue Engineering and Regenerative MedicineOrgan and Tissue Transplantation Research

XENOGENEIC EXTRACELLULAR MATRIX GRAFTS ELICIT A TH2-RESTRICTED IMMUNE RESPONSE1

Allman, Amy J., McPherson, Timothy B., Badylak, Stephen F., Merrill, Lisa C., Kallakury, Bhaskar, Sheehan, Christine, Raeder, Roberta H., Metzger, Dennis W.·2001·Transplantation
DOI 10.1097/00007890-200106150-00024
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Abstract

BACKGROUND: Porcine small intestinal submucosa (SIS) is an acellular, naturally derived extracellular matrix (ECM) that has been used for tissue remodeling and repair in numerous xenotransplantations. Although a vigorous immune response to xenogeneic extracellular matrix biomaterials is expected, to date there has been evidence for only normal tissue regeneration without any accompanying rejection. The purpose of this study was to determine the reason for a lack of rejection. METHODS: Mice were implanted s.c. with xenogeneic tissue, syngeneic tissue, or SIS, and the graft site analyzed histologically for rejection or acceptance. Additionally, graft site cytokine levels were determined by reverse transcriptase polymerase chain reaction and SIS-specific serum antibody isotype levels were determined by ELISA. RESULTS: Xenogeneically implanted mice showed an acute inflammatory response followed by chronic inflammation and ultimately graft necrosis, consistent with rejection. Syngeneically or SIS implanted mice, however, showed an acute inflammatory response that diminished such that the graft ultimately became indistinguishable from native tissue, observations that are consistent with graft acceptance. Graft site cytokine analysis showed an increase in interleukin-4 and an absence of interferon-gamma. In addition, mice implanted with SIS produced a SIS-specific antibody response that was restricted to the IgG1 isotype. Reimplantation of SIS into mice led to a secondary anti-SIS antibody response that was still restricted to IgG1. Similar results were observed with porcine submucosa derived from urinary bladder. To determine if the observed immune responses were T cell dependent, T cell KO mice were implanted with SIS. These mice expressed neither interleukin-4 at the implant site nor anti-SIS-specific serum antibodies but they did accept the SIS graft. CONCLUSIONS: Porcine extracellular matrix elicits an immune response that is predominately Th2-like, consistent with a remodeling reaction rather than rejection.

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Crossref · 10.1097/00007890-200106150-00024

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  • Evidence indicates that degradation products from ECM bioscaffolds condition antigen presentation and favor regulatory T lymphocyte induction and B lymphocyte tolerance, sustaining a pro-resolution set point that supports scaffold integration.

    “Collectively, the evidence indicates that degradation products from ECMbioscaffolds condition antigen presentation and favor regulatory T lymphocyte induction and B lymphocyte tolerance, sustaining a pro-resolution set point that supports scaffold integration [2,26,34].”

    From Immune Response to Extracellular Matrix Bioscaffolds: A Comprehensive Review (2025) · cites this paper as [34]

  • Xenogeneic ECM is commonly associated with a Th2-restricted humoral profile consistent with constructive outcome.

    “Although B lymphocytes can generate antibodies to residual antigens-potentially accelerating scaffold degradation [27]-xenogeneic ECM is commonly associated with a Th2-restricted humoral profile consistent with constructive outcome [2,34].”

    From Immune Response to Extracellular Matrix Bioscaffolds: A Comprehensive Review (2025) · cites this paper as [34]

  • The risk of immune responses from xenogeneic ECM can be greatly reduced by using proper preparation techniques.

    “While xenogeneic ECM has the potential to cause immune responses, this risk can be greatly reduced by using proper preparation techniques64; similar ECM scaffolds derived from animals are FDA-approved for clinical applications such as heart valve replacement, facial reconstruction, and osteopathic implants62,65.”

    From Towards organoid culture without Matrigel (2021) · cites this paper as [64]

  • Xenogeneic ECM has the potential to cause immune responses.

    “While xenogeneic ECM has the potential to cause immune responses, this risk can be greatly reduced by using proper preparation techniques64; similar ECM scaffolds derived from animals are FDA-approved for clinical applications such as heart valve replacement, facial reconstruction, and osteopathic implants62,65.”

    From Towards organoid culture without Matrigel (2021) · cites this paper as [64]

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Authors
Allman, A. J., McPherson, T. B., Badylak, S. F., Merrill, L. C., Kallakury, B., Sheehan, C., Raeder, R. H., & Metzger, D. W.
Affiliations
  • Albany Medical College (US)
  • University of Health Sciences and Pharmacy (US)
  • Purdue University West Lafayette (US)
Corresponding author
Metzger, Dennis W.
ORCID
Venue
Transplantation
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2001-06
Volume
71
Issue
11
Pages
1631-1640
ISSN
0041-1337 (ISSN-L)
DOI
10.1097/00007890-200106150-00024
OpenAlex
W1963940108
Cited by
388
References
28
Citations by year
2026: 4 · 2025: 5 · 2024: 11 · 2023: 10 · 2022: 14 · 2021: 21 · 2020: 18 · 2019: 16 · 2018: 11 · 2017: 18 · 2016: 16 · 2015: 19 · 2014: 27 · 2013: 31 · 2012: 15
FWCI
13.85
Type
journal article
Language
en
Open access
closed
Locations
  • Transplantation (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (5r01hl060359-04)
  • National Heart, Lung, and Blood Institute (HL60359)
Topics
  • Health Sciences › Medicine › Surgery › Xenotransplantation and immune response
  • Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
  • Health Sciences › Medicine › Transplantation › Organ and Tissue Transplantation Research
Keywords
porcine small intestinal submucosa, xenotransplantation, graft rejection, Th2 immune response, IL-4, interferon-gamma, IgG1 antibody response, T cell-dependent immunity, tissue remodeling, graft necrosis, chronic inflammation
MeSH terms
Animals, Antibody Formation, Urinary Bladder, Extracellular Matrix, Intestinal Mucosa, Intestine, Small, Mice, Inbred BALB C, Mice, Inbred C57BL, Mucous Membrane, RNA, Messenger, Swine, T-Lymphocytes, Transplantation, Heterologous, Transplantation, Isogeneic, Cytokines, Mice, Knockout, Th2 Cells, Mice

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