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Transplantation. 2002 Oct 15;74(7):1035-44.

Direct and indirect cross-tolerance of alloreactive T cells by dendritic cells retained in the immature stage.

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  • 1Department of Biomedical Sciences, Immunology Laboratory, Baylor College of Dentistry, Texas A&M University System Health Science Center, Dallas, TX 75246, USA. mnshirazi@tambcd.edu.

Abstract

BACKGROUND:

Rejection of allografts entails the direct and indirect cross-recognition of donor major histocompatibility complex molecules by recipient alloreactive T cells. The ability to manipulate the state of dendritic cell (DC) maturation in vitro has enabled us to induce tolerance specifically targeting the alloreactive T-cell compartment. In this study, the immunoregulatory effect of alloantigen presentation by ex vivo-generated donor and recipient DCs retained in immature stage was investigated.

METHODS:

Dendritic cell were generated by culturing monocytes with granulocyte-macrophage colony-stimulating factor and interleukin-4. Ex vivo-generated tolerogenic DCs were characterized by flow cytometry and confocal microscopy. Recipient T-cell responses to donor or recipient DCs loaded with donor-derived apoptotic cells were assessed in a two-step culture system.

RESULTS:

Dendritic cells maintained their phagocytic and endocytic activities, and had significantly reduced capacity to prime recipient T cells. Moreover, primary coculture of recipient T cells with donor tolerogenic DCs rendered alloantigen-specific T cells hyporesponsive to a subsequent challenge with donor immunogenic DCs as evidenced by decreased proliferation and cytokine secretion. Importantly, recipient tolerogenic DCs loaded with donor-derived apoptotic cells were able to cross-tolerize recipient T cells. This was revealed by alloantigen-specific T-cell hyporesponsiveness on restimulation with the recipient immunogenic DCs loaded with different tissue-derived apoptotic cells obtained from the same donor.

CONCLUSIONS:

Dendritic cells retained in immature stage induce direct and most importantly indirect cross-tolerance of alloantigen-specific T cells. It may be likely that administration of donor and/or recipient DCs could be one means with which to promote tolerance induction in acute and chronic phases of organ transplant.

[PubMed - indexed for MEDLINE]
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