Nasal application of a naturally processed and presented T cell epitope derived from TCR AV11 protects against adjuvant arthritis

Esther A. E. van Tienhoven, Chris P. M. Broeren, Alida Noordzij, Joseé P. A. Wagenaar, Willem van Eden and Marca H. M. Wauben

Institute of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, PO Box 80165, Yalelaan 1, 3508 TD Utrecht, The Netherlands

Correspondence to: M. H. M Wauben


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Reactivity towards TCR peptides plays an important role in the regulation of several experimental autoimmune diseases. In a previous paper, we showed the TCRAV11 usage by an arthritogenic T cell clone isolated from a rat with adjuvant arthritis (AA). Moreover, we identified three immunogenic peptides in AV11: AV11 24–40, 41–55 and 66–80. In the present study, we show that T cells directed towards all three epitopes are part of the immune repertoire. The strongest delayed-type hypersensitivity (DTH) reaction was observed against the peptide derived from the third framework region, peptide AV11 66–80. DTH reactions to this peptide were detectable in naive rats and increased significantly after AA induction. Interestingly, modulation of the AV11 66–80 T cell response by nasal AV11 66–80 administration resulted in reduced DTH responses and in a strong inhibition of AA. These findings suggest that during the natural course of AA, T cells directed towards the third framework region of AV11 do not have a disease regulatory function, but instead play a role in the deterioration of AA.

Keywords: autoimmunity, suppression, T lymphocytes, TCR


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
In autoimmune diseases, on the one hand, pathogenic self-reactivity of T cells plays an important role, while, on the other hand, self-reactivity is needed to regulate auto-aggressive responses (1). It has been shown that vaccination with modified auto-aggressive T cells protected against adjuvant arthritis (AA) and experimental autoimmune encephalomyelitis (EAE) (2,3). This suggested the activation of a T cell-specific regulatory T cell population. Indeed, anti-TCR-specific T cell responses were detected during the natural course of several autoimmune diseases (47). Moreover, it has been shown that T cells reactive to epitopes derived from the TCR of pathogenic T cells play a role in the regulation of autoimmunity (710). These findings indicate that although TCR-derived peptides are self-antigens, clonal deletion of TCR peptide-specific T cells in the thymus is not complete and that such cells are activated during autoimmune diseases. Furthermore, in the experimental autoimmune models EAE and collagen-induced arthritis (CIA), it appeared that autoreactive T cells used predominantly BV8S2 (TCR Vß8.2) (11,12). Interestingly, immunization with a peptide derived from the third framework region of BV8S2 prevented the induction of both EAE and CIA in mice (10).

The usage of TCR AV regions in experimental autoimmune diseases is less well documented. Previously, we showed the usage of AV11 by an arthritogenic T cell clone (A2b) specific for heat shock protein 60 (13). This AV11 sequence contains a number of immunogenic regions as determined by immunization with overlapping peptides. Furthermore, T cell lines reactive to these peptides recognized the recombinant AV11 protein (13). Interestingly, in SWR and DBA/1 mice, two polymorphisms in the AV11 gene have been observed to be associated with resistance to CIA induction (12,14). Moreover, vaccination with recombinant TCR AV11 decreased the arthritis incidence in CBA/1 mice (15).

In the present paper, the AA model was used to study naturally occurring T cell reactivity towards the AV11 immunogenic regions. The strongest T cell reactivity was observed with a peptide derived from the third framework region of AV11, AV11 66–80. Interestingly, nasal administration of AV11 66–80 led to a significant reduction of AV11 66–80-specific DTH reactions during AA and to a significant inhibition of disease. These data suggest that AV11 66–80-specific T cells play a role in the enhancement rather than in the down-regulation of the arthritic process.


    Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Animals
Male inbred Lewis rats (RT1L) were obtained from the University of Limburg (Maastricht, The Netherlands). Rats were 6–9 weeks old at the start of each experiment.

Peptides
AV11 26–40 (SITTTTVQWFRQNPR), 41–55 (GSLINLFYLVPGTKE), 66–80 (KERYSTLYISNAQVE) and myelin basic protein (MBP) 87–99 (VHFFKNIVTPRTP) were synthesized via automated multiple peptide synthesis (16). Ovalbumin (OVA) 323–339 (ISQAVHAAHAEINEAGR) and MBP 72–85 (QKSQRSQDENPV) were synthesised by standard solid-phase Fmoc chemistry (17). The peptides were purified by reversed-phase HPLC and analyzed via FAB/MS. The MBP peptides, used as marker peptides in the MHC binding assays, were biotinylated during peptide synthesis.

Delayed-type hypersensitivity (DTH)
Peptide was dissolved in PBS (1 mg/ml) and 100 µl was injected in one ear. PBS was injected in the contra-lateral ear. The DTH reaction was determined by measuring the ear thickness 48 h after injection with a pressure-sensitive micrometer. Data are expressed as the mean difference in ear thickness between the right and left ear in mm/100 ± SEM. The paired Student's t-test was performed on the mean difference to evaluate the effect of each peptide. The unpaired Student's t-test was performed to compare the mean differences in DTH reactions between the different groups.

Nasal peptide administration
Rats were lightly anesthetized with ether and 10 µl of 10 µg/µl peptide in PBS was administered nasally using a micropipette. This was done on days –15, –11, –7 and –3 preceding the induction of arthritis or EAE or the isolation of spleen and mandibular lymph nodes.

Induction and clinical evaluation of AA and EAE
AA was induced by intradermal injection in the base of the tail of 100 µl 5 mg/ml Mycobacterium tuberculosis (Mt, strain H37Ra; Difco, Detroit, MI) emulsified in incomplete Freund's adjuvant (IFA; Difco). To measure DTH reactions after induction of AA, rats were immunized with 10 mg/ml Mt. Rats were examined in a blind set-up for clinical signs of arthritis. Severity of arthritis was scored by grading each paw from 0 to 4 based on swelling, erythema and deformation of the joints as described earlier (18). EAE was induced by s.c. injection of 50 µl of a 1:1 emulsion of peptide MBP 72–85 (1 mg/ml) with 4 mg/ml Mt in IFA in each hind footpad. In a blind set-up, rats were examined for EAE and severity was scored on a scale from 0 to 4: 0, no signs; 1, limp tail; 2, hind leg weakness; 3, paraplegia; 4, front and hind leg paralysis, moribund condition.

T cell proliferation assay
Three days after the last nasal peptide administrations, rats were sacrificed, and the inguinal, popliteal and mandibular lymph nodes, and the spleen were isolated. Proliferation of 2x105 cells/well was measured in flat-bottom 96-well plates (Costar, Cambridge, MA) in triplicate cultures. The cells were cultured in culture medium [IMDM (Gibco/BRL, Gaithersburg, MD), supplemented with L-glutamine (2 mM), ß-mercaptoethanol (50 µM), penicillin (50 U/ml), streptomycin (50 U/ml) and 2% heat-inactivated normal rat serum] in the presence of a dose range of specific antigen or concanavalin A (2.5 µg/ml). Cultures were incubated at 37°C, 5% CO2 for 3 days and subsequently pulsed for 16–20 h with [3H]thymidine (0.4 µCi/well; Amersham, Little Chalfont, UK). [3H]Thymidine incorporation was measured using a liquid scintillation counter. Results are expressed as mean c.p.m. of triplicate cultures ± SD.

Peptide–MHC binding assay
The MHC class II–peptide binding studies were performed on affinity-purified detergent-solubilized MHC molecules as described previously (19). Briefly, rat RT1.BL and RT1.DL molecules were affinity purified from cell lysates of the MHC class II+ Z1a T cell line using the mAb OX6 and OX17. For competition studies purified RT1.Bl (3 µM) or RT1.Dl (1 µM) was incubated with respectively 100 nM of biotinylated marker peptide MBP 72–85 or 87–99 and a dose range of unlabeled competitor peptide for 40 h at room temperature at pH 5 in the presence of a protease inhibitor mix. The MHC–peptide mixtures were analyzed by SDS–PAGE under non-reducing conditions and followed by Western blotting. Biotinylated peptides were visualized through enhanced chemiluminescence (Western blot ECL kit; Amersham, Arlington Heights, IL). The IC50 value is the concentration of competitor peptide in µM resulting in 50% inhibition of the binding of 100 nM biotinylated marker peptide to 3 µM RT1.BL or 1 µM RT1.DL as calculated with the molecular Analyst software (BioRad, Hercules, CA).


    Results
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Natural processing and presentation of TCR AV11 epitopes during AA
Previously, we have identified three immunogenic regions of the TCR {alpha} chain of A2b: AV11 26–40, 41–55 and 66–80 (13). T cell responses, induced after immunization with synthetic peptides comprised of sequences derived from these immunogenic regions, appeared to be MHC class II restricted (13). These findings raised the question whether during AA the AV11 peptides were naturally processed and presented in a MHC class II-restricted manner. To study this, we evaluated the presence of AV11-specific T cells after the onset of AA. 14 Days after AA induction, the three immunogenic AV11 peptides were tested for DTH reactivity. As shown in Table 1Go, all three AV11 peptides induced a significant DTH reaction, whereas no DTH reaction was observed with a highly immunogenic control peptide. This indicated that AV11 T cell epitopes are naturally processed and presented in vivo, and that AV11 specific T cells are part of the T cell repertoire.


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Table 1. Natural occurrence of AV11 peptide specific T cells
 
MHC binding affinity of AV11 epitopes
Previously, we demonstrated that blocking with OX6 (anti-RT1.BL) abrogated the proliferative response of AV11 26–40-specific T cells, while OX17 (anti-RT1.DL) inhibited AV11 41–55- and 66–80-specific T cell responses (13). Here, we determined in a competitive peptide–MHC binding assay the MHC binding affinity of AV11 26–40 for RT1.BL, and of AV11 41–55 and 66–80 for RT1.DL. Figure 1Go shows the competitive inhibition of binding of the biotinylated marker peptides to purified MHC class II molecules by the addition of increasing concentrations of non-labeled AV11 peptides. AV11 26–40, which induced only a mild DTH reaction, appeared to be a strong binder for RT1.BL (IC50 16–32 µM). Both AV11 41–55 and 66–80 induced a strong DTH reaction, and appeared to be a strong RT1.DL binder (IC50 8–16 µM) and an intermediate RT1.DL binder (32–64µM) respectively. These data indicate that there is no clear correlation between the MHC binding affinity of the peptide and the observed DTH reaction.



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Fig. 1. Binding affinity of AV11 peptides to MHC class II molecules. MHC RT1.BL (3 µM) was incubated with biotinylated MBP 72–85 (100 nM) and a dose range of unlabeled AV11 26–40. RT1.DL (1 µM) was incubated with biotinylated MBP 87–99 (100 nM) and a dose range of AV11 41–55 or 66–80. The peptide–MHC mixtures were analyzed by SDS–PAGE and Western blotting, and the biotinylated peptides were visualized through ECL.

 
Increased T cell responses to AV11 66–80 during AA
Based on the strongest DTH reaction, AV11 66–80 was selected for further studies. First, we analyzed the DTH reaction towards AV11 66–80 in naive animals. As shown in Table 2Go, a mild DTH reaction was already observed in naive rats. Next, we analyzed whether AV11 66–80-specific T cell responses were increased before the onset of clinical disease. Indeed, a strong DTH reaction was observed 9 days after AA induction, when no clinical signs of arthritis could be observed yet (Table 2Go). This DTH reaction was comparable with the DTH reaction observed 14 days after AA induction (29 ± 2, Table 1Go), when all rats showed clinical signs. These data indicate that AV11 66–80-specific T cells already became activated before clinical onset of AA.


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Table 2. AV11 66–80-specific DTH responses
 
Reduced DTH responses and protection against AA after nasal administration of AV11 66–80
The early activation of AV11 66–80-specific T cells during the onset of AA raised the question whether such T cells play a role in deterioration or amelioration of the arthritogenic process. To study this, we applied AV11 66–80 nasally 4 times at 3-day intervals before disease induction and investigated the AV11 66–80-specific DTH reaction 9 days after AA induction. As shown in Table 2Go, nasal administration reduced the DTH response significantly to almost undetectable levels. Next, we evaluated the effect of nasal AV11 66–80 administration on the development of AA. As a control, we used the OVA 323–339 peptide. The peptides were applied nasally 4 times at 3-day intervals, starting 14 days before AA induction. Nasal administration of AV11 66–80 almost completely inhibited arthritis development, whereas administration of OVA 323–339 had no influence on AA development (Fig. 2AGo). As an additional clinical parameter, the percentage of weight loss was evaluated. As shown in Fig. 2Go(B), OVA 323–339-treated animals had a marked weight loss during active arthritis, while the AV11 66–80-treated animals only gained weight. To test whether the disease inhibitory effect of AV11 66–80 was specific for AA, we analyzed the effect of nasal peptide administration on the induction of EAE in Lewis rats. At first, we measured the presence of AV11 66–80-specific T cells during the onset of EAE, as EAE is induced in the presence of the same adjuvant used for AA induction (Mt/IFA). As shown in Table 2Go, a strong DTH response was detected during the onset of EAE. Interestingly in contrast to the effect on AA, nasal peptide administration did not effect the development of EAE (Fig. 3A and BGo).



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Fig. 2. Protection against AA after nasal administration of AV11 66–80. The peptides OVA 323–339 and AV11 66–80 were dissolved in 10 µg/µl PBS and 10 µl was applied nasally 4 times at 3-day intervals, starting 14 days before AA was induced. AA was induced by s.c. injection of 100 µl 5 mg/ml Mt dissolved in IFA. (A) Arthritis score. (B) Percent weight loss. Each experimental group consisted of n = 5 rats. Data are derived from one representative experiment out of two. Data are expressed as mean ± SEM. {blacksquare}, AV11 66–80; {blacktriangleup}, OVA 323–339.

 


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Fig. 3. No protection against EAE after nasal administration of AV11 66–80. Peptides were nasally administered as described in the legend of Fig. 2Go. EAE was induced 3 days after the last nasal peptide administration. (A) EAE score. (B) Percent weight loss. Each experimental group consisted of n = 4 rats. Data are expressed as mean ± SEM. {blacksquare}, AV11 66–80; {blacktriangleup}, OVA 323–339.

 
No deletion of AV11 66–80-specific T cells after nasal administration
Since we observed a clear inhibition of AV11 66–80 DTH responses after nasal peptide administration, we analyzed whether this was due to deletion of AV11 66–80-specific T cells. Therefore, 3 days after the last nasal administration of AV11 66–80 or control peptide OVA 323–339, spleen and mandibular lymph nodes were isolated and tested in a proliferation assay. In the mandibular lymph nodes, no proliferative responses were detected to the administered peptides (Fig. 4aGo). However, in the spleen, peptide-specific proliferative responses were detected (Fig. 4bGo). This indicated that nasal peptide administration led to a specific T cell activation and did not delete peptide specific T cells.



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Fig. 4. Proliferative responses after nasal peptide administration. Three days after the last nasal administration of AV11 66–80 or OVA 323–339, mandibular lymph nodes (A) or spleen-derived cells (B) were isolated and tested in a proliferation assay. The cells of each experimental group (n = 4 rats) were pooled and presented as the mean proliferative response of triplicate cultures ± SD.

 

    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
In this paper, we report that T cells specific for three peptides derived from the AV11 region of an arthritogenic T cell clone are naturally present in the T cell repertoire of Lewis rats, as measured by DTH reactions during AA. The peptide AV11 26–40 induced only a mild DTH reaction, while peptides AV11 41–55 and 66–80 induced strong DTH reactions after AA induction. AV11 41–55 is localized in the second CDR and it has been described that in multiple sclerosis patients, CDR2 peptides derived from various variable regions of the TCR ß chain appeared to be immunogenic (20). Furthermore, a CDR2 peptide derived from VB8S2 was found to be naturally processed during EAE and protected against EAE (4). Our AV11 41–55 data confirm the finding that CDR2 peptides are in general immunogenic (20).

AV11 66–80 is localized in the third framework region of the {alpha} chain. Interestingly, a polymorphism in this framework region of AV11 was suggested to play an essential role in resistance and susceptibility to arthritis induction (14). Moreover, it has been described that TCR peptides derived from the third framework region of both mouse and rat BV8S2 protected against experimental autoimmunity (6,10).

The observation that AV11-specific T cells were present in the immune repertoire indicated that these cells were not deleted in the thymus. T cell selection in the thymus is controlled by the number of peptide–MHC complexes, the affinity of the peptides for the MHC molecules and the affinity of the TCR for the MHC–peptide complex (21). The mild DTH reaction to AV11 26–40 could be due to the rather high affinity of the peptide for RT1.BL. However, AV11 66–80 induced the strongest DTH reaction and appeared to be a strong RT1.DL binder. Therefore, the lack of deletion of these AV11-specific T cells should be due to either the low frequency of specific epitope–MHC complexes within the thymus or the relatively low TCR affinity for the specific peptide–MHC complexes.

Since AV11 66–80 showed the strongest DTH reaction at day 14 after disease induction, this peptide was selected for further study. Both the DTH reactions at days 9 and 14 were significantly increased as compared with naive animals. This indicated that already during the induction phase of AA, before clinical signs of AA were visible, activation of TCR AV11 66–80-specific T cells had occurred. Taking into account the relatively high MHC binding affinity of the peptide, this could imply that a relative low number of MHC–AV11 66–80 complexes is present in naive rats due to, for example, crypticity of the epitope, while during the strong inflammatory process of AA, AV11 66–80 is unveiled. This would be in agreement with the observation by Di Rosa et al. showing that strong inflammatory processes can induce a change in the processing machinery of antigen-presenting cells (APC) (22). Alternatively, it is possible that in naive rats, due to the low frequency of AV11-bearing T cells, the number of specific MHC class II–AV11 66–80 complexes is low. During AA, an expansion and subsequent turnover of AV11+ T cells could result in uptake and presentation of AV11 peptides by professional APC (23) or in presentation of TCR peptides by MHC class II molecules on activated T cells (24).

To study the role of AV11 66–80-specific T cells during AA, we applied AV11 66–80 nasally before AA induction. This resulted in a strong inhibition of the AV11 66–80-specific DTH reaction and in protection against AA. The protection was specific, since nasal AV11 66–80 application could not protect against EAE. Moreover, we observed that 3 days after the last nasal peptide administration, a clear peptide specific proliferative response was present in the spleen. Although we cannot exclude that after AA induction, AV11 66–80-specific T cells were deleted, the proliferative response in the spleen directly after nasal administration argues against AV11 66–80-specific T cell deletion as the main protective mechanism. In several other autoimmune models, the induction of T cells producing regulatory cytokines (e.g. IL-4, IL-10 and transforming growth factor-ß) after nasal administration has been observed (2529). As other groups indicated that TCR peptide-specific T cells could play a role in the down-regulation of autoimmune diseases (3032), it could well be possible that nasal AV11 66–80 administration led to enhanced activation of the already pre-existing regulatory T cell response. However, the reduction of the naturally occurring AV11 66–80 DTH response during AA after nasal AV11 66–80 administration indicated that nasal administration modulated the natural AV11 66–80-specific T cell response. This finding, together with the finding that AV11 66–80-specific T cells were already activated before the clinical onset of arthritis, suggests that the naturally occurring AV11 66–80-specific T cell response during AA plays a role in the exacerbation or perpetuation of AA, rather than in the down-regulation of the disease process. This hypothesis is further substantiated by our recent findings indicating that 11 out of 36 rats immunized with AV11 66–80 in a Th1 skewing adjuvant (dimethyl-dioctadecyl ammonium bromide) developed arthritis (33). Moreover, three out of five rats injected i.v. with AV11 66–80-specific T cells also developed arthritis, indicating the T cell-mediated character of the AV11 66–80-induced arthritis. Enhancement of experimental autoimmune diseases after TCR peptide immunizations has also been described by others (3436). Yamamura and co-workers showed that an {alpha} chain TCR CDR3 peptide derived from an encephalitogenic T cell clone did not only enhance MBP- or proteolipid protein-induced EAE, but also AA (36). However, these findings and our findings are in contrast with data described by other groups, showing that deletion or neonatal tolerization of TCR-specific T cells or modulation of the TCR peptide-specific Th1 response towards a Th2 response all resulted in exacerbation of the experimental autoimmune diseases EAE and diabetes (3741). There is no easy explanation why the outcome of TCR-based therapies is so variable. Differences could amongst others be based on the activation of pre-existing versus induced TCR-specific T cells, the timing of the intervention, the different model systems or the presence of MHC class II on rat T cells, which in contrast to mouse T cells express MHC class II (24).

In conclusion, we showed that AV11 peptide-specific T cells are part of the normal immune repertoire. Moreover, our data suggests that T cells specific for the third framework region AV11 66–80 play a role in the deterioration of AA, rather than in the down-regulation of AA. Although the underlying mechanism has not been elucidated, these data urge to caution with respect to TCR-based immunotherapy of autoimmune diseases.


    Acknowledgments
 
We would like to thank M. J. F. van der Cammen and M. C. Grosfeld for their excellent contribution to the peptide–MHC binding assays, and Dr R. van der Zee for peptide synthesis. The research of E. A. E. van T. has been made possible by a grant of the Nationaal Reumafonds. The research of C. P. M. B. has been made possible by NWO (901-06-213). The research of M. H. M. W. has been made possible by a fellowship of the Royal Netherlands Academy of Arts and Sciences.


    Abbreviations
 
AA adjuvant arthritis
APC antigen-presenting cell
CDR complementarity-determining region
CIA collagen-induced arthritis
DTH delayed-type hypersensitivity.
EAE experimental autoimmune encephalomyelitis
IFA incomplete Freund's adjuvant
MBP myelin basic protein
Mt Mycobacterium tuberculosis
OVA ovalbumin

    Notes
 
Transmitting editor: J.-F. Bach

Received 20 March 2000, accepted 6 September 2000.


    References
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. Van Eden, W., Van der Zee, R., Paul, A. G. A., Prakken, B. J., Wendling, U., Anderton, S. M. and Wauben, M. H. M. 1998. Do heat shock proteins control the balance of T cell regulation in inflammatory diseases? Immunol. Today 19:303.[ISI][Medline]
  2. Holoshitz, J., Naparstek, Y., Ben-Nun, A. and Cohen, I. R. 1983. Lines of T lymphocytes induce or vaccinate against autoimmune arthritis. Science 219:56.[ISI][Medline]
  3. Lider, O., Reshef, T., Beraud, E., Ben-Nun, A. and Cohen, I. R. 1988. Anti-idiotypic network induced by T cell vaccination against experimental autoimmune encephalomyelitis. Science 239:181.[ISI][Medline]
  4. Offner, H., Hashim, G. A. and Vandenbark, A. A. 1991. T cell receptor peptide therapy triggers autoregulation of experimental encephalomyelitis. Science 251:430.[ISI][Medline]
  5. Kumar, V. and Sercarz, E. E. 1993. The involvement of T-cell receptor peptide specific regulatory CD4+ T-cells in recovery from antigen-induced autoimmune disease. J. Exp. Med. 178:909.[Abstract]
  6. Vainiene, M., Celnik, B., Vandenbark, A. A., Hashim, G. A. and Offner, H. 1996. Natural immunodominant and experimental autoimmune encephalomyelitis-protective determinants within the Lewis rat V beta 8.2 sequence include CDR2 and framework 3 idiotopes. J. Neurosci. Res. 43:137.[ISI][Medline]
  7. Elias, D., Tikochinski, Y., Frankel, G. and Cohen, I. R. 1999. Regulation of NOD mouse autoimmune diabetes by T cells that recognize a TCR CDR3 peptide. Int. Immunol. 11:957.[Abstract/Free Full Text]
  8. Vandenbark, A. A., Hashim, G. and Offner, H. 1989. Immunization with a synthetic T-cell receptor V-region peptide protects against experimental autoimmune encephalomyelitis. Nature 341:541.[ISI][Medline]
  9. Haqqi, T. M., Qu, X. M., Anthony, D., Ma, J. and Sy, M. S. 1996. Immunization with T cell receptor Vb chain peptides deletes pathogenic T cells and prevents the induction of collagen-induced arthritis in mice. J. Clin. Invest. 97:2849.[Abstract/Free Full Text]
  10. Kumar, V., Aziz, F., Sercarz, E. and Miller, A. 1997. Regulatory T cells specific for the same framework 3 region of the Vß8.2 chain are involved in the control of collagen II-induced arthritis and experimental autoimmune encephalomyelitis. J. Exp. Med. 10:1725.
  11. Acha-Orbea, H., Mitchell, D. J., Timmermann, L., Wraith, D. C., Tausch, G. S., Waldor, M. K., Zamvil, S. S., McDevitt, H. O. and Steinman, L. 1988. Limited heterogeneity of T cell receptors from lymphocytes mediating autoimmune encephalomyelitis allows specific immune intervention. Cell 54:263.[ISI][Medline]
  12. Osman, G. E., Toda, M., Kanagawa, O. and Hood, L. E. 1993. Characterization of the T-cell receptor repertoire causing collagen arthritis in mice. J. Exp. Med. 177:387.[Abstract]
  13. Broeren, C. P. M., Lucassen, M. A., van Stipdonk, M. J. B., van der Zee, R., Boog, C. J. P., Kusters, J. G. and van Eden, W. 1994. CDR1 T-cell receptor ß-chain peptide induces major histocompatibility complex class II-restricted T–T cell interactions. Proc. Natl Acad. Sci. USA 91:5997.[Abstract]
  14. Osman, G. E., Hannibal, M. C., Anderson, J. P., Cheunsuk, S., Lasky, S. R., Liggitt, H. D., Ladiges, W. C. and Hood, L. E. 1999. T-cell receptor vbeta deletion and valpha polymorphism are responsible for the resistance of SWR mouse to arthritis induction. Immunogenetics 49:764.[ISI][Medline]
  15. Rosloniec, E. F., Brand, D. D., Whittington, K. B., Stuart, J. M., Ciubotaru, M. and Ward, E. S. 1995. Vaccination with a recombinant V{alpha} domain of a TCR prevents the development of collagen-induced arthritis. J. Immunol. 155:4504.[Abstract]
  16. Van der Zee, R., Anderton, S. M., Buskens, C. A., F.Alonso de Velasco, E. V and Van Eden, W. 1994. Heat shock protein T-cell epitopes as immunogenic carriers in subunit vaccines. In Proc. 23rd Eur. Peptide Symp: ESCOM, p. 841. H. L. S. Maia, Leiden.
  17. Steward, J. M. and Young, J. D. 1984. Solid Phase Peptide Synthesis. Pierce Chemical, Rockford, IL.
  18. Trentham, D. E., Townes, A. S. and Kang, A. H. 1977. Autoimmunity to type II collagen an experimental model of arthritis. J. Exp. Med. 146:857.[Abstract]
  19. Joosten, I., Wauben, M. H. M., Holewijn, M. C., Reske, K., Pedersen, L. O., Roosenboom, C. F., Hensen, E. J., Van Eden, W. and Buus, S. 1994. Direct binding of autoimmune disease related T cell epitopes to purified Lewis rat MHC class II molecules. Int. Immunol. 6:751.[Abstract]
  20. Bourdette, D. N., Chou, Y. K., Whitham, R. H., Buckner, J., Kwon, H. J., Nepom, G. T., Buenafe, A., Cooper, S. A., Allegretta, M., Hashim, G. A., Offner, H. and Vandenbark, A. A. 1998. Immunity to T cell receptor peptides in multiple sclerosis. III. Preferential immunogenicity of complementarity-determining region 2 peptides from disease-associated T cell receptor BV genes. J. Immunol. 161:1034.[Abstract/Free Full Text]
  21. Kruisbeek, A. M. and Amsen, D. 1996. Mechanisms underlying T-cell tolerance. Curr. Opin. Immunol. 8:233.[ISI][Medline]
  22. Di Rosa, F. and Barnaba, V. 1998. Persisting viruses and chronic inflammation: understanding their relation to autoimmunity. Immunol. Rev. 164:17.[ISI][Medline]
  23. Kumar, V. 1998. Determinant spreading during experimental autoimmune encephalomyelitis: is it potentiating, protecting or participating in the disease? Immunol. Rev. 164:73.[ISI][Medline]
  24. Broeren, C. P. M., Wauben, M. H. M., Lucassen, M. A., van Meurs, M., van Kooten, P. J. S., Boog, C. J. P., Claassen, E. and van Eden, W. 1995. Activated rat T cells synthesize and express functional major histocompatibility class II antigens. Immunology 84:193.[ISI][Medline]
  25. Chen, Y., Kuchroo, V. K., Inobe, J., Hafler, D. A. and Weiner, H. L. 1994. Regulatory T cell clones induced by oral tolerance: suppression of autoimmune encephalomyelitis. Science 265:1237.[ISI][Medline]
  26. Dick, A. D., Cheng, Y. F., Liversidge, J. and Forrester, J. V. 1994. Intranasal administration of retinal antigens suppresses retinal antigen-induced experimental autoimmune uveoretinitis. Immunology 82:625.[ISI][Medline]
  27. Tian, J., Atkinson, M. A., Clare-Salzler, M., Herschenfeld, A., Forsthuber, T., Lehmann, P. V. and Kaufman, D. L. 1996. Nasal administration of glutamate decarboxylase (GAD65) peptides induces Th2 responses and prevents murine insulin-dependent diabetes. J. Exp. Med. 183:1561.[Abstract]
  28. Haque, M. A., Yoshino, S., Inada, S., Nomaguchi, H., Tokunaga, O. and Kohashi, O. 1996. Suppression of adjuvant arthritis in rats by induction of oral tolerance to mycobacterial 65-kDa heat shock protein. Eur. J. Immunol. 26:2650.[ISI][Medline]
  29. Shi, F. D., Li, H., Wang, H., Bai, X., van der Meide, P. H., Link, H. and Ljunggren, H. G. 1999. Mechanisms of nasal tolerance induction in experimental autoimmune myasthenia gravis: identification of regulatory cells. J. Immunol. 162:5757.[Abstract/Free Full Text]
  30. Kumar, V., Stellrecht, K. and Sercarz, E. 1996. Inactivation of T cell receptor peptide-specific CD4 regulatory T cells induces chronic experimental autoimmune encephalomyelitis (EAE). J. Exp. Med. 184:1609.[Abstract]
  31. Siklodi, B., Jacobs, R., Vandenbark, A. A. and Offner, H. 1998. Neonatal exposure of TCR BV8S2 transgenic mice to recombinant TCR BV8S2 results in reduced T cell proliferation and elevated antibody response to BV8S2, and increased severity of EAE. J. Neurosci. Res. 52:750.[ISI][Medline]
  32. Kumar, V. and Sercarz, E. 1998. Induction or protection from experimental autoimmune encephalomyelitis depends on the cytokine secretion profile of TCR peptide-specific regulatory CD4 T cells. J. Immunol. 161:6585.[Abstract/Free Full Text]
  33. Van Tienhoven, E. A. E., Van Kooten, P. J. S., Veenstra, J. G., Van der Hage, M. H., Van Eden, W. and Broeren, C. P. M. 2000. Induction of experimental autoimmune arthritis by a public epitope of the T cell receptor variable {alpha} domain of an arthritogenic T cell clone. Eur. J. Immunol. 30:2164[ISI][Medline]
  34. Desquenne-Clark, L., Esch, T. R., Otvos, L., Jr and Heber-Katz, E. 1991. T-cell receptor peptide immunization leads to enhanced and chronic experimental allergic encephalomyelitis. Proc. Natl Acad. Sci. USA 88:7219.[Abstract]
  35. Tanuma, N., Abe, S., Shin, T., Kojima, T. Ishihara, Y., Arai, Y., Toyoshima, S. and Matsumoto, Y. 1996. Pretreatment with T cell receptor peptides using conventional immunization protocol does not induce effective protection against autoimmune encephamyelitis. Cell. Immunol. 168:85.[ISI][Medline]
  36. Yamamura, T., Geng, T.-C., Kozovska, M. F., Yokoyama, K., Cohen, I. R. and Tabira, T. 1996. An alpha-chain TCR CDR3 peptide can enhance EAE induced by myelin basic protein or proteolipid protein. J. Neurosci. Res. 45:706.[ISI][Medline]
  37. Kumar, V., Stellrecht, K. and Sercarz, E. 1996. Inactivation of T cell receptor peptide-specific CD4 regulatory T cells induces chronic experimental autoimmune encephalomyelitis (EAE). J. Exp. Med. 184:1609.[Abstract]
  38. Siklodi, B., Jacobs, R., Vandenbark, A. A. and Offner, H. 1998. Neonatal exposure of TCR BV8S2 transgenic mice to recombinant TCR BV8S2 results in reduced T cell proliferation and elevated antibody response to BV8S2, and increased severity of EAE. J. Neurosci. Res. 52:750.[ISI][Medline]
  39. Kumar, V. and Sercarz, E. 1998. Induction or protection from experimental autoimmune encephalomyelitis depends on the cytokine secretion profile of TCR peptide-specific regulatory CD4 T cells. J. Immunol. 161:6585.[Abstract/Free Full Text]
  40. Waisman, A., Ruiz, P. J., Hirschberg, D. L., Gelman, A., Oksenberg, J. R., Brocke, S., Mor, F., Cohen, L. R. and Steinman, L. 1996. Suppressive vaccination with DNA encoding a variable region gene of the T cell receptor prevents autoimmune encephalomyelitis and activates Th2 immunity. Nat. Med. 2:899.[ISI][Medline]
  41. Elias, D., Tikochinski, Y., Frankel, G. and Cohen, I. R. 1999. Regulation of NOD mouse diabetes by T cells that recognize a TCR CDR3 peptide. Int. Immunol. 11:957.[Abstract/Free Full Text]




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