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LETTERS TO THE EDITOR |
The Schepens Eye Research Institute, Harvard Medical School, 20 Staniford Street, Boston, MA 02114
Previous studies by our laboratory suggest that tolerogenic APC influence CD1d-restricted NKT cells to facilitate tolerance toward foreign Ags (1, 2, 3). Therefore, we chose to investigate the requirement of NKT cells for tolerance to self-Ags, using a model of myelin basic protein (MBP)-induced experimental autoimmune encephalomyelitis (EAE). We initially hypothesized that C57BL/6 wild-type mice would be relatively resistant to MBP-EAE, whereas NKT-deficient mice would not. However, we observed that wild-type C57BL/6 mice developed moderate EAE whereas NKT-deficient mice (both J
281and CD1d knockouts) did not. Although the difference between the wild-type and knockouts was not reported in our article, the fact that C57BL/6 mice developed disease at all was entirely unexpected. As indicated by Furlan in his letter to the Editor, C57BL/6 mice are reported to be relatively resistant to EAE induced via active immunization with MBP. We appreciate this historical perspective, but remain confident in our unexpected results, as they were repeated in several experiments with C57BL/6 mice both from Taconic and our own animal colony (derived from Taconic, C57BL/6-NTac). In the majority of our studies we observed a moderate form of disease (mean clinical score of 2.0), manifested by tail flaccidity and hind limb weakness, both of which are unmistakable. Moreover, four different laboratory members confirmed the degree of ascending paralysis in blinded fashion.
The ability of our laboratory to generate MBP-EAE in C57BL/6 mice via active immunization may be explained by a number of factors. First, the original experiments that described strain-related susceptibility to MBP-EAE were conducted two decades ago. It is reasonable to suggest that genetic mutations may accumulate from two decades worth of inbreeding, viral and bacterial infections of breeder stocks, and numerous other environmental pressures, which may all contribute to a change in susceptibility to any given disease. Second, early studies that defined genetic susceptibility used preparations of myelin, Bordetella pertussis toxin, and H37Ra Mycobacterium tuberculosis that most likely differ from the commercial sources available today. Third, we used commercially available whole bovine MBP (not MBP84–104 peptide) that is enriched to at least 50%. It is possible that the EAE that we report may have arisen, in part, due to other myelin-associated proteins in the preparation (i.e., MOG, PLP, etc.) as well as unidentified components that may provide additional adjuvant-like effects. Thus, changes in genetic factors and reagents and their effects on the susceptibility to MBP-EAE may not have become apparent until now, as most investigators would be unlikely to choose MBP as an Ag, given current dogma.
Lastly, Furlan states, "the reference cited in Materials and Methods [Bettelli et al., 1998] is not appropriate, since it refers to EAE obtained in a different mouse strain with a different Ag." In Materials and Methods, we stated, "EAE was induced with an adaptation of the method of Bettelli et al." (4). Although we used a different Ag (hence, our adaptation), the mouse strain was indeed the same, C57BL/6. Other treatments including pertussis and H37Ra were similar, if not identical.
We thank the Editor for the opportunity to respond.
References
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