| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Department of Microbiology-Immunology and the Interdepartmental Immunobiology Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611
MHC class II (MHC II)-restricted T cell responses are a common driving force of autoimmune disease. Accordingly, numerous therapeutic strategies target CD4+ T cells with the hope of attenuating autoimmune responses and restoring self-tolerance. We have previously reported that i.v. treatment with Ag-pulsed, ethylenecarbodiimide (ECDI)-fixed splenocytes (Ag-SPs) is an efficient protocol to induce Ag-specific tolerance for prevention and treatment of experimental autoimmune encephalomyelitis (EAE). Ag-SPs coupled with peptide can directly present peptide:MHC II complexes to target CD4+ T cells in the absence of costimulation to induce anergy. However, Ag-SPs coupled with whole protein also efficiently attenuates Ag-specific T cell responses suggesting the potential contribution of alternative indirect mechanisms/interactions between the Ag-SPs and target CD4+ T cells. Thus, we investigated whether MHC II compatibility was essential to the underlying mechanisms by which Ag-SP induces tolerance during autoimmune disease. Using MHC-deficient, allogeneic, and/or syngeneic donor Ag-SPs, we show that MHC compatibility between the Ag-SP donor and the host is not required for tolerance induction. Interestingly, we found that ECDI treatment induces apoptosis of the donor cell population which promotes uptake and reprocessing of donor cell peptides by host APCs resulting in the apparent MHC II-independent induction of tolerance. However, syngeneic donor cells are more efficient at inducing tolerance, suggesting that Ag-SPs induce functional Ag-SP tolerance via both direct and indirect (cross-tolerance) mechanisms leading to prevention and effective treatment of autoimmune disease.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by the United States Public Health Service, National Institutes of Health Grants NS-026543, NS-030871-13, and NS-048411-02, National Multiple Sclerosis Society Grant RG 3793-A-7, and by support from the Myelin Repair Foundation.
2 Address correspondence and reprint requests to Dr. Stephen D. Miller, Department of Microbiology-Immunology, Northwestern University Medical School, 303 East Chicago Avenue, Chicago, IL 60611. E-mail address: s-d-miller{at}northwestern.edu
3 Abbreviations used in this paper: EAE, experimental autoimmune encephalomyelitis; 7-AAD, 7-aminoactinomycin D; Ag-SP, Ag-coupled splenocyte; BM-DC, bone marrow-dendritic cell; CIITA, class II transcriptional activator; DAPI, 4',6'-diamidino-2-phenylindole; DTH, delayed-type hypersensitivity; ECDI, ethylenecarbodiimide; LN, lymph node; MBP, myelin basic protein; MHC I, MHC class I: MHC II, MHC class II; MOG, myelin oligodendrocyte protein; MS, multiple sclerosis; MSCH, mouse spinal cord homogenate; PLP, proteolipid protein; PTx, pertussis toxin; Tg, transgenic.
This article has been cited by other articles:
|
|
 |
|
  X. Luo, K. L. Pothoven, D. McCarthy, M. DeGutes, A. Martin, D. R. Getts, G. Xia, J. He, X. Zhang, D. B. Kaufman, et al. ECDI-fixed allogeneic splenocytes induce donor-specific tolerance for long-term survival of islet transplants via two distinct mechanisms PNAS, September 23, 2008; 105(38): 14527 - 14532. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. W. Wegmann, C. R. Wagner, R. H. Whitham, and D. J. Hinrichs Synthetic Peptide Dendrimers Block the Development and Expression of Experimental Allergic Encephalomyelitis J. Immunol., September 1, 2008; 181(5): 3301 - 3309. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
