ITIM-dependent negative signaling pathways for the control of cell-mediated xenogeneic immune responses

被引:15
作者
del Rio, Maria-Luisa [1 ,2 ]
Seebach, Joerg D. [3 ,4 ]
Fernandez-Renedo, Carlos [2 ]
Rodriguez-Barbosa, Jose-Ignacio [1 ]
机构
[1] Univ Leon, Inst Biomed, Transplantat Immunobiol Sect, E-24071 Leon, Spain
[2] Castilla & Leon Transplantat Reg Agcy, Leon Univ Hosp, Leon 24071, Spain
[3] Univ Hosp, Dept Med Specialties, Div Immunol & Allergy, Geneva, Switzerland
[4] Fac Med, Geneva, Switzerland
基金
瑞士国家科学基金会;
关键词
cellular rejection; co-inhibitory receptors and ligands; immunoreceptor tyrosine-based inhibitory motif; killer immunoglobulin-like receptor; macrophages; NK cells; T cells; xenotransplantation; PORCINE ENDOTHELIAL-CELLS; HUMAN NK CYTOTOXICITY; HLA-G; XENOGRAFT REJECTION; TRANSGENIC PIGS; B-LYMPHOCYTE; T-CELLS; IMMUNOLOGICAL BARRIERS; EXPRESSION; RECEPTOR;
D O I
10.1111/xen.12049
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Xenotransplantation is an innovative field of research with the potential to provide us with an alternative source of organs to face the severe shortage of human organ donors. For several reasons, pigs have been chosen as the most suitable source of organs and tissues for transplantation in humans. However, porcine xenografts undergo cellular immune responses representing a major barrier to their acceptance and normal functioning. Innate and adaptive xenogeneic immunity is mediated by both the recognition of xenogeneic tissue antigens and the lack of inhibition due to molecular cross-species incompatibilities of regulatory pathways. Therefore, the delivery of immunoreceptor tyrosine-based inhibitory motif (ITIM)-dependent and related negative signals to control innate (NK cells, macrophages) and adaptive T and B cells might overcome cell-mediated xenogeneic immunity. The proof of this concept has already been achieved in vitro by the transgenic overexpression of human ligands of several inhibitory receptors in porcine cells resulting in their resistance against xenoreactivity. Consequently, several transgenic pigs expressing tissue-specific human ligands of inhibitory coreceptors (HLA-E, CD47) or soluble competitors of costimulation (belatacept) have already been generated. The development of these robust and innovative approaches to modulate human anti-pig cellular immune responses, complementary to conventional immunosuppression, will help to achieve long-term xenograft survival. In this review, we will focus on the current strategies to enhance negative signaling pathways for the regulation of undesirable cell-mediated xenoreactive immune responses.
引用
收藏
页码:397 / 406
页数:10
相关论文
共 79 条
[1]   Elimination of porcine hemopoietic cells by macrophages in mice [J].
Abe, M ;
Cheng, J ;
Qi, J ;
Glaser, RM ;
Thall, AD ;
Sykes, M ;
Yang, YG .
JOURNAL OF IMMUNOLOGY, 2002, 168 (02) :621-628
[2]   Macrophage depletion prolongs discordant but not concordant islet xenograft survival [J].
Andres, A ;
Toso, C ;
Morel, P ;
Bosco, D ;
Bucher, P ;
Oberholzer, J ;
Mathe, Z ;
Mai, G ;
Wekerle, T ;
Berney, T ;
Bühler, LH .
TRANSPLANTATION, 2005, 79 (05) :543-549
[3]   Xenogeneic transplantation [J].
Auchincloss, H ;
Sachs, DH .
ANNUAL REVIEW OF IMMUNOLOGY, 1998, 16 :433-470
[4]  
Baehr A, 2011, XENOTRANSPLANTATION, V18, P271
[5]   The SIRP family of receptors and immune regulation [J].
Barclay, AN ;
Brown, MH .
NATURE REVIEWS IMMUNOLOGY, 2006, 6 (06) :457-464
[6]   CD200 and membrane protein E interactions in the control of myeloid cells [J].
Barclay, AN ;
Wright, GJ ;
Brooke, G ;
Brown, MH .
TRENDS IN IMMUNOLOGY, 2002, 23 (06) :285-290
[7]   Clearance of mobilized porcine peripheral blood progenitor cells is delayed by depletion of the pragocytic reticuloendothelial system in baboons [J].
Basker, M ;
Alwayn, IPJ ;
Buhler, L ;
Harper, D ;
Abraham, S ;
Gray, HK ;
DeAngelis, H ;
Awwad, M ;
Down, J ;
Rieben, R ;
White-Scharf, ME ;
Sachs, DH ;
Thall, A ;
Cooper, DKC .
TRANSPLANTATION, 2001, 72 (07) :1278-1285
[8]   Inhibitory ITAMs as novel regulators of immunity [J].
Blank, Ulrich ;
Launay, Pierre ;
Benhamou, Marc ;
Monteiro, Renato C. .
IMMUNOLOGICAL REVIEWS, 2009, 232 :59-71
[9]   CD47 (integrin-associated protein) engagement of dendritic cell and macrophage counterreceptors is required to prevent the clearance of donor lymphohematopoietic cells [J].
Blazar, BR ;
Lindberg, FP ;
Ingulli, E ;
Panoskaltsis-Mortari, A ;
Oldenborg, PA ;
Iizuka, K ;
Yokoyama, WM ;
Taylor, PA .
JOURNAL OF EXPERIMENTAL MEDICINE, 2001, 194 (04) :541-549
[10]   Overcoming the immunological barriers to xenotransplantation [J].
Bradley, JA .
TRANSPLANTATION, 1999, 68 (01) :9-11