Bone marrow lacking integrin expression facilitates an enhanced susceptibility to EAE in the xenogeneic bone marrow chimera☆
Introduction
Multiple Sclerosis (MS) is a debilitating, neurodegenerative disease effecting ~ 2.5 million people, world wide (www.nationalmssociety.org). The most common form of MS manifests itself in a relapsing-remitting form (RRMS). An uncertain combination of genetic and environmental factors present in the pre-pathogenic time frame can predispose a person to develop MS. Although factors predisposing the CNS to autoimmune attack are not fully understood, specific events such as upper respiratory tract infection have been observed to occur prior to an MS relapse (Gilden, 2005, Tauber et al., 2007). Therefore conditions exist in which an activated immune response might predispose the CNS to clinically relevant attack. In this regard, we have shown experimentally that activated non-myelin-specific T cells augment the accumulation of transplanted bone marrow-derived APC into the CNS within an acute, seven day time frame and predispose the mouse CNS to EAE in a xenogeneic rodent transplantation model (Subramanian et al., 2001). Rapid accumulation of bone marrow-derived cells (BMC) in the CNS is substantially earlier than in the absence of non-myelin-specific T cells (Jones et al., 1996) and weeks earlier than previously reported for chimeric rats (Hickey and Kimura, 1988, Hinrichs et al., 1987). Because the early accumulation of BMC greatly elevated the susceptibility to EAE (Jones et al., 2003a) we set out to identify the subset of rat BMC that is responsible for populating the mouse CNS under the modulating influence of non-myelin T cells.
Previously we have observed that BMC accumulate within the CNS as CD11b/c expressing APC (Subramanian et al., 2001). CD11b is a developmental phenotype marker for the myelomonocytic lineage and CD11c is expressed by dendritic APC in the CNS (Pashenkov et al., 2003, Polfliet et al., 2002). Thus, CD11b/c expression may play a role in the development and function of antigen-presenting myelomonocytic lineage BMC in the CNS. An additional marker, CD49d, may also be important in modulating the accumulation of rat BM into the spinal cord since CD49d directs mobilization of hematopoietic cells from the bone marrow into the blood (Mohle et al., 1995, Papayannopoulou and Nakamoto, 1993, Papayanopoulou and Craddock, 1997, Turner et al., 1995) and it is a developmental marker for dendritic APC derived from circulating blood monocytes (Puig-Kroger et al., 2000). We hypothesized that expression of CD11b/c and/or CD49d would distinguish rat bone marrow cells that differed in their capacities to populate the CNS and promote EAE disease following transplantation into immunodeficient recipients, C.B-17 scid/scid mice. We compared CD11b/c-depleted versus enriched BMC for their capacity to induce disease. We found sequential depletion of BMC expressing CD11b/c and CD49d identified dual-negative BMC (lacking expression of both integrins CD11b/c and CD49d) as precursors to disease. These results demonstrate a pre-pathogenic capacity for integrin-negative bone marrow to promote subsequent disease induction, and suggest that conditions regulating these BM precursors and their progeny in the pre-pathogenic time frame may be involved in susceptibility to and severity of acute disease episodes.
Section snippets
Animals
Six to eight week old female Lewis rats were obtained from Harlan Sprague Dawley. Inbred female C.B-17 scid/scid (SCID) mice (8–11 weeks old) were obtained from the severe combined immunodeficient (SCID) mouse breeding facility within the Veterinary Medical Unit at the Portland VA Medical Center. Animal care was in accordance with institutional guidelines.
Rat T cell lines
Eight rats (age 8–9 weeks) per line were each immunized by subcutaneous injection with a synthetic peptide of myelin basic protein (BP)
BMC depleted of CD11b/c positive cells induced paralytic EAE
Due to the potential role for bone marrow-derived CD11b/c-positive CNS cells in T cell mediated autoimmune disease, we evaluated EAE disease course and severity in mice with transplanted BMC fractionated based on their expression of CD11b/c (Fig. 1). CD11b/c-enriched BMC (CD11b/c(+)) possessed an approximately 2–3 fold higher proportion of CD11b/c positive cells (57 ± 12%, n = 4, Fig. 1B) compared to unsorted (CD3-depleted) BMC (20 ± 6%, n = 4). CD11b/c-positive cells were virtually absent from the
Discussion
Herein, our experimental manipulations have demonstrated particular conditions in the pre-pathogenic time frame that can modulate and predispose mice to a high susceptibility and future development of clinical pathology. Specifically, recipients of transplanted CD11b/c(−) BMC and non-myelin-specific activated T cells acquired severe disease as compared to recipients of CD11b/c(+) BM and recipients without non-myelin-specific T cells. Transplanted CD11b/c(−) BMC developed into CD11b/c(+) cells
Acknowledgments
This work was supported in part by the Office of Research and Development, Medical Research Service, Department of Veterans Affairs; and NIH-NINDS (RJ, NM).
References (32)
- et al.
Allogeneic T cells induce rapid CD34+ cell differentiation into CD11c + CD86+ cells with direct and indirect antigen-presenting function
Blood
(2006) - et al.
Regulation of myeloid development and function by colony stimulating factors
Dev. Comp. Immunol.
(2004) - et al.
Relative susceptibility of SJL/J and B10.S mice to experimental allergic encephalomyelitis is correlated with high and low responsiveness to myelin basic protein
J. Neuroimmunol.
(1991) - et al.
CD8 + TCR+ and CD8 + TCR-cells in whole bone marrow facilitate the engraftment of hematopoietic stem cells across allogeneic barriers
Immunity
(1999) Infectious causes of multiple sclerosis
Lancet Neurol.
(2005)- et al.
Expression of the CD11/CD18, leukocyte adhesion molecule 1, and CD44 adhesion molecules during normal myeloid and erythroid differentiation in humans
Blood
(1990) - et al.
Kinetics of central nervous system microglial and macrophage engraftment: analysis using a transgenic bone marrow transplantation model
Blood
(1997) IL-3 in dendritic cell development and function: a comparison with GM-CSF and IL-4
Immunobiology
(2004)- et al.
Biology of human hematopoietic stem and progenitor cells present in circulation
Arch. Med. Res.
(2003) - et al.
The role of perivascular and meningeal macrophages in experimental allergic encephalomyelitis
J. Neuroimmunol.
(2002)
Regulation of mature T cell homeostasis
Semin. Immunol.
Role of macrophages/microglia in multiple sclerosis and experimental allergic encephalomyelitis
J. Mol. Med.
Basic principles of immunological surveillance of the normal central nervous system
Glia
Perivascular microglial cells of the CNS are bone marrow-derived and present antigen in vivo
Science
Transfer of experimental allergic encephalomyelitis to bone marrow chimeras: endothelial cells are not a restricting element
J. Exp. Med.
Phenotype and function of hematopoietic-derived cells in the CNS of SCID mouse-Lewis rat bone marrow chimeras
J. Neurosci. Res.
Cited by (2)
Early influx of macrophages determines susceptibility to experimental allergic encephalomyelitis in Dark Agouti (DA) rats
2011, Journal of NeuroimmunologyCitation Excerpt :Moreover, only DA rats developed EAE after the transfer of (AO × DA) F1 hybrid encephalitogen specific cells into sub-lethally irradiated parental AO and DA hosts (Mostarica-Stojkovic et al., 1992). Using xenogeneic rodent transplant model, Jones' group (Jones et al., 2003; Robinson et al., 2008) have reported that bone marrow derived antigen presenting cells (APCs) lacking integrin expression facilitate EAE induction. The role of blood-borne and perivascular meningeal macrophages in the early phase of EAE induction has been suggested by Tran et al. (1998) who demonstrated that blocking macrophage function in the inductive phase of EAE in mice prevented the invasion of the CNS by autoreactive T cells.
MR imaging of inflammation during myelin-specific T cell-mediated autoimmune attack in the EAE mouse spinal cord
2010, Molecular Imaging and Biology
- ☆
This work was supported by the U.S. Department of Veterans Affairs Merit Review program (RJ), the National Institutes of Health (RJ) and the Nancy Davis Center Without Walls (RJ, DB).