Induction of xenogeneic neonatal tolerance to transgenic human leukocyte antigen class I grafts

Steven H. Borenstein, Kesheng S. Tao, Ningjie Hu, Lori J. West, John W. Chamberlain

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Background. The immune response against xenografts is vigorous and poorly controlled with conventional immunosuppressants. Therefore, success in xenotransplantation will depend on developing additional approaches such as induction of immunologic unresponsiveness or tolerance. Although classic protocols of neonatal tolerance induction in mice are very tolerogenic in many allogeneic models, they have generally failed in xenogeneic models. The purpose of these studies was to determine whether failure results from an intrinsic property of xenogenic major histocompatibility complex (MHC) molecules themselves or, instead, is caused by some limitation in species-specific molecular interactions distinct from the polymorphic domains of xenogenic MHC molecules. Methods. Our approach was to test the ability of lymphoid cells from a transgenic (Tg) mouse donor expressing a xeno-MHC class I molecule encoding the polymorphic α1/α2 for human leukocyte antigen (HLA)-B7 to induce neonatal tolerance in non-Tg syngeneic C57BL/6 recipients. Because the donor and recipient strains are genetically identical (C57BL/6, H-2b) except for Tg human MHC HLA-B7, any species-specific molecular incompatibility in this mouse anti-human class I xeno-combination that could potentially interfere with induction of tolerance has been eliminated. Results. Our results show that HLA-B7 Tg-, but not C57BL/6 syngeneic-, injected neonates were unresponsive as adults to HLA-B7-expressing target cells in vitro and specifically accepted HLA-B7-expressing Tg skin grafts. In addition, neonatal injection of donor cells resulted in peripheral chimerism. Conclusions. These experiments demonstrate that, as long as species-specific molecular interactions are maintained, recognition of the polymorphic domains of xenogeneic MHC does not represent a barrier to neonatal tolerance induction.

Original languageEnglish (US)
Pages (from-to)844-852
Number of pages9
JournalTransplantation
Volume78
Issue number6
DOIs
StatePublished - Sep 27 2004
Externally publishedYes

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HLA Antigens
Major Histocompatibility Complex
Transplants
Heterologous Transplantation
Chimerism
Immunosuppressive Agents
Heterografts
Transgenic Mice
Lymphocytes
Skin
Injections

ASJC Scopus subject areas

  • Transplantation
  • Immunology

Cite this

Induction of xenogeneic neonatal tolerance to transgenic human leukocyte antigen class I grafts. / Borenstein, Steven H.; Tao, Kesheng S.; Hu, Ningjie; West, Lori J.; Chamberlain, John W.

In: Transplantation, Vol. 78, No. 6, 27.09.2004, p. 844-852.

Research output: Contribution to journalArticle

Borenstein, Steven H. ; Tao, Kesheng S. ; Hu, Ningjie ; West, Lori J. ; Chamberlain, John W. / Induction of xenogeneic neonatal tolerance to transgenic human leukocyte antigen class I grafts. In: Transplantation. 2004 ; Vol. 78, No. 6. pp. 844-852.
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