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,
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Multiple Sclerosis Research Laboratory, Department of Neurology and Baylor-Methodist Multiple Sclerosis Center,
Department of Microbiology and Immunology, and
Neurology Research Laboratory, Veterans Affairs Medical Center, Baylor College of Medicine, Houston, TX 77030
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Anti-idiotypic T cell responses can be activated in vivo by repeated immunization (T cell vaccination) with autologous T cells that are inactivated by irradiation or chemical treatment (5). T cell vaccination has been shown to effectively treat various experimental autoimmune diseases in animals, including experimental autoimmune encephalomyelitis, an animal model for multiple sclerosis (MS) (6, 7). Several lines of indirect evidence suggest that the anti-idiotypic T cell responses induced by T cell vaccination target specifically at the T cells used for immunization in recognition of target TCR. First, the protective immunity conferred by T cell vaccination is specific for the disease that autoimmune T cells used for vaccination are able to induce (6, 7). Second, anti-idiotypic T cells isolated from immunized rodents recognize specifically the immunizing T cell clones/lines but not T cells expressing distinct TCR structural features (6, 7). It is thought that TCR determinants recognized by anti-idiotypic T cells most likely reside within CDR3 or CDR2, as predicted by characteristic sequence diversity within these regions (8, 9, 10, 11). Recently, T cell vaccination has been tested in patients with MS (12) where autoreactive T cell responses to myelin basic protein (MBP) may play an important role in the disease processes (13, 14, 15, 16). In two clinical trials, we demonstrated that s.c. inoculations with irradiated autologous MBP-reactive T cell clones induced substantial anti-idiotypic T cell responses in patients with MS, which correlated with progressive depletion of circulating MBP-reactive T cells used for vaccination (Ref. 17 , Y. C. Q. Zang et al., manuscript in preparation). Although the treatment efficacy remains to be determined in controlled clinical trials, the preliminary clinical results suggest that depletion of MBP-reactive T cells may alter favorably the clinical course of the disease. The clinical benefit of T cell vaccination was evident by a reduction in rate of relapse and disability score by neurologic evaluations as well as decreased brain lesion scores by magnetic resonance imaging studies in patients with relapsing-remitting MS (Ref. 17 , Zang et al., manuscript in preparation). The anti-idiotypic T cell lines isolated from patients immunized with irradiated MBP-reactive T cell clones were predominantly CD8+ cytotoxic T cells that specifically recognized and lysed the immunizing T cell clones but not unrelated autologous T cells (12, 18).
This study was undertaken to define the recognition pattern and functional properties of CD8+ anti-idiotypic T cells induced by T cell vaccination. A panel of anti-idiotypic T cell lines was isolated from immunized MS patients using overlapping TCR peptides corresponding to CDR2 and CDR3 of the immunizing MBP-reactive T cell clones. Based on the sequence diversity and immunogenic properties of CDR2 and CDR3, the idiotypic determinants recognized by the anti-idiotypic T cells are most probably localized within these regions. The use of TCR peptides over the irradiated T cells as stimulator offered several advantages. First, the TCR peptides were designed as 9-mers to selectively isolate CD8+ anti-idiotypic T cells, as the majority of the anti-idiotypic T cells induced by T cell vaccination were previously shown to express the CD8 phenotype and exhibit MHC class I restriction (12, 18). Therefore, the resulting anti-idiotypic T cell lines isolated by the 9-mer TCR peptides most likely represent the same T cell population elicited by T cell vaccination. Second, immunization with irradiated MBP-reactive T cell clones also induced the T cell reactivity to other surface molecules present on the immunizing T cells. For the purpose of this study, the use of TCR peptides would selectively activate the anti-idiotypic T cells, sparing unrelated T cells that may obscure anti-idiotypic T cell responses. The study described herein provided important experimental evidence indicating that T cell vaccination induces CD8+ cytotoxic anti-idiotypic T cell responses that are preferentially directed at CDR3 sequences of the immunizing MBP-reactive T cell clones. CDR2 contains cryptic determinants and is less immunogenic. The findings are important in our understanding of the mechanism underlying in vivo idiotypic regulation that can be boosted by T cell vaccination.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Medium used for cell culture was Aim-V serum-free medium (Life Technologies, Grand Island, NY). Recombinant human IL-2 was purchased from Boehringer Mannheim (Indianapolis, IN). The immunodominant peptide (residues 83–99) of MBP was kindly provided by Dr. Stefen Boheme (Neurocrine Biosciences, San Diego, CA). A set of overlapping TCR peptides of 9 aa in length was synthesized by Chiron Technologies (San Diego, CA). The purity of the peptides was greater than 95%.
Myelin-reactive T cell clones
A panel of six MBP-reactive T cell clones were generated from three patients with MS using a microculture system combined with split-well technique (12, 15, 16). Briefly, PBMC were plated out at 200,000 cells/well in U-bottom 96-well plates in the presence of MBP83–99 peptide (10 µg/ml) in AIM-V serum-free medium. Seven days later, the cultures were restimulated with MBP83–99 peptide and irradiated autologous PBMC as a source of APC. After another 7 days, the cultures were tested for specific response to MBP83–99 peptide in a proliferation assay. The positively identified T cell lines were cloned using limiting dilution assay in the presence of PHA-protein (PHA-P) at 2 µg/ml. Cultures were fed with fresh medium every 3–4 days. Growth positive wells were tested for specific reactivity to the MBP83–99 peptide in proliferation assays. The resulting MBP83–99-specific T cell clones were further characterized and used for T cell vaccination.
TCR V gene analysis of MBP83–99-reactive T cell clones
TCR V gene rearrangements of the immunizing MBP-reactive T cell
clones were analyzed using reverse-transcribed PCR. TCR 
- and
ß-chain genes were amplified and directly sequenced as previously
described (19, 20). Briefly, total RNA was extracted from
106 cells of each
MBP83–99-reactive T cell clone using RNeasy mini
kit (Qiagen, Santa Clarita, CA). First-strand cDNA reverse transcribed
from total RNA was subject to PCR amplification with a set of primers
specific for TCR V and Vß gene families whose sequences were
published previously (19, 20). The amplified PCR products
were separated in a 1% agarose gel by electrophoresis and stained with
ethidium bromide. The visualized PCR products were cut and purified
subsequently using a QIAquick gel extraction kit (Qiagen) before
sequence analysis. The purified PCR products were directly sequenced
with the T7 sequencing kit (Pharmacia, Uppsala, Sweden). A total of 1.5
µg of template was sequenced with 2 pmol of the corresponding V gene
primer using the method of dideoxy chain termination
(21).
Immunization of MS patients with irradiated autologous MBP-reactive T cell clones
Three patients with clinically definite MS confirmed by magnetic resonance imaging were included in this study (22). They were diagnosed as having relapsing-remitting MS for more than 2 years, and mean baseline Expanded Disability Scale Score (EDSS) was 1.67. The patients had not taken any immunomodulatory drugs at least 3 mo before the study. Immunizations with irradiated autologous MBP83–99-reactive T cell clones was performed as previously described (12, 17). Briefly, MBP83–99-reactive T cell clone was activated and expanded in the presence of PHA 7 days before injection. T cells were then irradiated at 10,000 rads (a 60Co source) and thoroughly washed with sterile saline. A total of 2 x 107 cells of each T cell clone was resuspended in 1 ml of sterile saline and was injected s.c. in the arms. The immunization was repeated every 2 mo for 8 mo to achieve an adequate immune response as defined by the proliferation of PBMC to the immunizing T cell clone(s). The protocol was approved by the Institutional Human Subjects Committee at Baylor College of Medicine. Consent forms were obtained from the patients after explaining the experimental procedures. The patients were evaluated for adverse events and disability score (the EDSS) before and after each immunization. Gadolinium-enhanced MRI scans were performed before and at different time points after immunization. The clinical and radiographic evaluation was part of a separate clinical study (Zang et al., manuscript in preparation).
The generation and characterization of anti-idiotypic T cell lines raised against TCR peptides and the immunizing T cell clones
To generate anti-idiotypic T cell lines recognizing the TCR
peptides, PBMC obtained from the immunized patients were plated out at
100,000 cells/well in U-bottomed plates (Costar, Cambridge, MA) in the
presence of 10 µg/ml respective peptides (40 wells for each peptide).
Seven days later, all cultures were restimulated with the corresponding
peptide in the presence of irradiated autologous PBMC as a source of
APC. After another week, each culture was examined for specific
proliferation to the TCR peptide in proliferation assays. Briefly, each
well was split into four aliquots (
104
cells/aliquot) and cultured in duplicate in the presence of
105 APC pulsed with the TCR peptide or a control
peptide, respectively. Cells were cultured for 72 h and pulsed
with [3H]thymidine (Amersham, Arlington
Heights, IL) at 1 µCi/well during the last 16 h of the culture.
Cells were then harvested and [3H]thymidine
incorporation was measured in a betaplate counter (Wallac, Turku,
Finland). A T cell line was considered to be specific for the peptide
when the cpm were greater than 1500 and exceeded the reference cpm (in
the presence of the control peptide) by at least three times. T cells
generated at this stage were considered as short-term T cell lines and
were expanded for further characterization.
The protocol for the generation of anti-idiotypic T cell lines
recognizing the original immunizing MBP-reactive T cell clones was
described previously (12, 18). Briefly, fresh PBMC (5
x 104 cells/well) from the immunized patients
were plated out in the presence of irradiated immunizing T cells as
stimulator cells (5 x 104 cells/well).
Seven days later, cultures were then restimulated with irradiated
immunizing T cells and supplemented with human rIL-2. On day 14, the
growth-positive wells were examined for their inhibitory effect on the
proliferation of the immunizing MBP-reactive T cell clones
(15). For this purpose, the wells were split and 40,000
cells from each well were lightly irradiated (2,000 rads) and used
as effector cells. The 40,000 immunizing MBP-reactive T cells
were used as responder cells in the presence of MBP and APC in a
proliferation assay as described above. The percent inhibition
was calculated as [1 - (cpm of MBP-reactive T cell clones in the
presence of irradiated regulatory T cells/cpm of MBP-reactive T cell
clones in the absence of irradiated regulatory T cells)] x 100%. T
cell lines exhibiting more than 50% specific inhibition on
MBP-reactive T cell clones but not on autologous PHA-stimulated T cells
(control T cells) were selected for further characterization.
As a general rule, the identified anti-idiotypic T cell lines were expanded in two stimulation cycles (7 days for each cycle) with the corresponding peptides or irradiated T cell clones under the experimental conditions described above. The cell lines were then tested in proliferation assays to reconfirm the reactivity to the TCR peptides or the immunizing T cell clones before further characterization.
Anti-idiotypic T cell reactivity to TCR peptides and immunizing T cell clones
A total of 20,000 cells of each TCR-specific T cell lines was cultured with irradiated autologous PBMC (100,000 cells/well) as a source of APC in the presence of a corresponding TCR peptide (10 µg/ml), or irradiated immunizing T cells (20,000 cells per well), respectively. Cells were cultured for 72 h, and the cell proliferation was measured in [3H]thymidine incorporation assays as described above.
Cytotoxicity assay
Immunizing T cell clones and control clones were labeled by incubating the cells with 200 µCi of 51Cr for 45 min. Cells were washed subsequently and used as target cells in a chromium release assay. The effector (anti-idiotypic T cells) to target (the immunizing clones and control T cells) ratio was 10. After incubation at 37°C for 4 h, supernatants were harvested and radioactivity was measured in a gamma counter. The maximum and spontaneous chromium release was determined in wells containing detergent or medium alone. The percent specific cytolysis was calculated as [(experimental release - spontaneous release)/(maximum release - spontaneous release)] x 100%.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A panel of six MBP-reactive T cell clones was generated from three
MS patients with relapsing-remitting MS. They expressed the CD4
phenotype and recognized the 83–99 immunodominant peptide of MBP in
the context of the DR2 (DRB1*1501) or DR4 molecules (Table I
). As shown in Tables
II and III,
all the MBP-reactive T cell clones derived from three patients
displayed distinct TCR V and Vß genes. These T cell clones were
used for T cell vaccination according to the protocol employed in
previous clinical trials (see Materials and Methods). Each
patient received a total of four s.c. inoculations with two autologous
MBP-reactive T cell clones (2 x 107
cells/clone) at a 2-mo interval. The T cell responses to the autologous
immunizing T cell clones were examined before and after each
immunization.
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A, the
proliferative responses to irradiated immunizing T cell clones were
increased progressively with each immunization and exceeded
substantially the baseline value (>10-fold) after the fourth
immunization in all three patients. The increased response to the
immunizing T cells was found to inversely correlate with a decline of
the frequency of circulating MBP-reactive T cells in the immunized
patients (Fig. 1B). The results have confirmed that the
anti-idiotypic T cell responses directed at MBP-reactive T cells
can be induced in patients with MS by repeated immunizations with
irradiated T cell clones (12, 17, 18).
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Based on the extreme sequence diversity in CDR3, and to a lesser
degree in CDR2 (8), it was predicted that the idiotypic
determinants responsible for triggering anti-idiotypic T cells
might reside within these TCR regions. A set of overlapping peptides
was synthesized to correspond to the CDR2 and CDR3 sequences of both
- and ß-chains of the immunizing T cell clones. As the majority of
the anti-idiotypic T cells induced by T cell vaccination were found
to express the CD8 phenotype and recognize immunizing T cells in the
context of MHC class I molecules (12, 17, 18), 9-mer
peptides were synthesized and used to selectively isolate
CD8+ anti-idiotypic T cells induced by T cell
vaccination. As all immunizing T cell clones had 15–16 aa in the CDR2
and less than 8–9 aa in the CDR3, two overlapping CDR2 peptides and
one CDR3 peptide were made for each - or ß-chain. TCR-specific T
cell lines were generated from PBMC specimens obtained from three
patients 1–2 mo after the forth immunization, at which time
substantial T cell responses to the immunizing T cell clones were
documented (Fig. 1
).
As shown in Fig. 2, the majority of
anti-idiotypic T cell lines obtained from immunized patients
reacted with the CDR3 peptides (17/21 resulting T cell lines),
suggesting the preferential recognition of the CDR3 determinants. In
contrast, only four of the TCR-specific T cell lines (4/21) were found
to recognize CDR2 pep- tides. The resulting CDR2- and
CDR3-specific T cell lines expressed exclusively the CD8 phenotype.
However, not all TCR peptides used here were equally immunogenic in the
generation of TCR-specific T cell lines. In patient MS1, CDR3-specific
T cell lines were isolated from both immunizing T cell clones, while in
MS2 and MS3 only the TCR peptides derived from one of the immunizing T
cell clones were effective in eliciting anti-idiotypic T cell
responses.
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Recognition pattern and cytotoxicity of TCR3-specific anti-idiotypic T cell lines
The obtained TCR-specific T cell lines were further characterized
for their reactivity to the autologous immunizing T cell clones used
for T cell vaccination. Of 17 CDR3-specific T cell lines examined,
eight T cell lines recognized the autologous immunizing MBP-reactive T
cell clones but not autologous nonspecific T cells. The result of a
representative experiment is presented in Fig. 3. In contrast, none of the CDR2-specific
T cell lines obtained reacted with the immunizing T cell clones (data
not shown). All eight CDR3-specific T cell lines examined exhibited
specific cytotoxic activity against the original immunizing T cell
clones but not autologous PHA-induced T cells in chromium-release
assays (four representative T cell lines shown in Fig. 4). The cytotoxicity could be blocked by
an Ab directed at MHC class I (W6/32) but not class II molecules (HB55)
(Fig. 4). The results indicate that a significant proportion of
anti-idiotypic T cell lines raised against the CDR3 peptides but
not the CDR2 peptides may represent the CD8+
anti-idiotypic T cell populations induced by T cell
vaccination.
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As the CDR3-specific T cell lines recognized the original
immunizing MBP-reactive T cells, it remained to be tested whether the
anti-idiotypic T cell lines raised against original immunizing T
cell clones would recognize the TCR peptides. To this end, a small
panel of eight anti-idiotypic T cell lines were generated from PBMC
of two MS patients (MS1 and MS3) using the original immunizing
MBP-reactive T cell clones as stimulator (see Materials and
Methods). As shown in Fig. 5, the
resulting CD8+ anti-idiotypic T cell lines
specifically reacted with the original MBP-reactive T cell clones but
not unrelated MBP-reactive T cell clones of autologous origin that were
not used for immunization. Of eight T cell lines examined, five lines
reacted specifically with the CDR3 peptides derived from CDR3 of the
immunizing MBP-reactive T cell clones (Fig. 5). The remaining T cell
lines exhibited no reactivity to any of the TCR peptides, suggesting
that at least some of the CDR3 peptides contained idiotypic
determinant(s) recognized by CD8+
anti-idiotypic T cells induced by T cell vaccination.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The CDR3-specific T cell lines obtained from immunized patients represent distinct anti-idiotypic T cell populations from those reported in other studies where anti-idiotypic T cells were isolated from nonimmunized healthy individuals (3, 4). They recognize CDR3 peptides in the context of MHC class I molecules, and differ in MHC restriction from anti-idiotypic T cells reported by Jiang et al. (23, 24). The CD8+ cytotoxic anti-idiotypic T cell responses described here are not readily detectable in nonimmunized patients and healthy individuals, as reported previously (3, 4). It is conceivable that the unique sequence diversity and structural properties within CDR3 may contribute to its immunogenicity and preferred role in eliciting anti-idiotypic T cell responses in T cell vaccination. On the contrary, CDR2-specific T cells generated from these immunized MS patients resemble anti-idiotypic T cells found in nonimmunized individuals as they do not recognize the original MBP-reactive T cell clones or lines (3, 4), which is consistent with our hypothesis that they may recognize cryptic determinants within CDR2 and are not involved in T cell vaccination.
There are several issues emerged from the study. 1) The results of the
study do not completely rule out the possibility that the TCR regions
other than CDR3 and CDR2, such as CDR1 and the framework regions, may
also be involved in the anti-idiotypic T cell responses induced by
T cell vaccination. This possibility may account partially for the
observation that not all cytotoxic anti-idiotypic T cell lines
isolated from the immunized patients recognize the CDR2 and CDR3
peptides. However, they are unlikely to represent dominant idiotypic
determinants responsible for the anti-idiotypic T cell responses in
T cell vaccination as these regions are less variable and encoded by
germline sequences to which the immune system may be tolerant. 2) The
study also indicates that not all CDR3 or CDR2 peptides examined are
equally effective in activating anti-idiotypic T cell responses in
the immunized patients. Some of the CDR3 and CDR2 peptides failed to
elicit sufficient anti-idiotypic T cell responses. It is likely
that some of the TCR peptides may have poor immunogenic properties for
the following reasons. The CDR3 peptides used in these experiments were
single 9-mer peptides corresponding to the V-J or Vß-Dß-Jß
junctional regions of a given T cell clone, excluding the flanking
residues. As a result, the T cell recognition of some idiotypic
determinants may be affected by the lacking of certain flanking
residue(s) that may contribute to the T cell recognition. An
alternative explanation is that immunization to some of these
MBP-reactive T cell clones was not equally sufficient. This possibility
is supported by relatively lower anti-idiotypic T cell responses
(stimulation index) to the immunizing T cell clones in patients MS2 and
MS3. 3) At this time, it is unclear whether there are functional
differences in cytotoxic anti-idiotypic T cell response between MS
patients and normal individuals. The likelihood of a functional deficit
in the idiotypic regulatory network needs to be exploited in future
investigations.
There are several existing models that may explain how the idiotypic determinants of target TCR are presented to and recognized by anti-idiotypic T cells. There is experimental evidence indicating that peptides of cell surface molecules are often presented by MHC class I molecules, and that peptide binding motifs for MHC class I molecules have been identified (25, 26). Several recent studies have demonstrated that endogenous TCR peptides can be presented by self-MHC to anti-idiotypic T cells (11, 27). The CD8+ cytotoxic anti-idiotypic T cells seem to be characteristically associated with and elicited by T cell vaccination (12, 18). It is remarkable that the immune system immobilizes the CD8+ cytotoxic anti-idiotypic T cells as a specific regulatory component in restraining clonal activation and expansion of MBP-reactive T cells, an exaggerated in vivo condition created by T cell vaccination. Alternatively, the route of administration, the amount of T cells administered and potentially altered biological/immunologic properties of the cell surface molecules by irradiation may all account for selective activation of CD8+ cytotoxic anti-idiotypic T cell responses seen in T cell vaccination.
The CD8+ cytotoxic anti-idiotypic T cell responses to MBP-reactive T cells induced by T cell vaccination may favorably alter the clinical course of MS. This is suggested by an inverse correlation of anti-idiotypic T cell responses with depletion of circulating MBP-reactive T cells and with clinical improvement seen in immunized patients with MS (Ref. 17 , Zang et al., manuscript in preparation). However, the clinical effect of T cell vaccination needs to be proven in a controlled clinical trial. The findings described herein have important implications in advancement of the current T cell vaccination protocol by designing a more practical peptide-based immunization approach. Although CDR2 peptides have been used in clinical trials to suppress MBP-reactive T cells (28), our findings suggest that immunization with short CDR3 peptides may be more effective in depleting circulating MBP-reactive T cells by inducing CD8+ cytotoxic anti-idiotypic T cell responses. On the other hand, the use of CDR3 peptides significantly limits the applicability of the peptide-based immunization approach because CDR3 sequences are extremely diverse and unique for each T cell clone. As we demonstrated recently, common sequence motif(s) does exist within CDR3 of MBP-reactive T cells derived from different MS patients that uniformly recognize the immunodominant 83–99 peptide of MBP in the context of DR2 (DRB1*1501) molecules (29). Further investigations in exploring common CDR3 motifs among the immunodominant MBP-reactive T cells in a selected group of MS patients may provide a solution to overcome these limitations.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Jingwu Zhang, Department of Neurology, Baylor College of Medicine, 6501 Fannin Street, NB302, Houston, TX 77030.
3 Abbreviations used in this paper: CDR, complementarity-determining region; MBP, myelin basic protein; MS, multiple sclerosis; MBP83–99, the immunodominant 83–99 peptide of MBP.
Received for publication October 8, 1999. Accepted for publication February 1, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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gene rearrangement in T cells recognizing an immunodominant peptide of myelin basic protein in DR2 patients with multiple sclerosis. Int. Immunol. 10:991.This article has been cited by other articles:
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  J. Hong, Y. C. Q. Zang, H. Nie, and J. Z. Zhang CD4+ regulatory T cell responses induced by T cell vaccination in patients with multiple sclerosis PNAS, March 28, 2006; 103(13): 5024 - 5029. [Abstract] [Full Text] [PDF]
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R. Hohlfeld and H. Wekerle Autoimmune concepts of multiple sclerosis as a basis for selective immunotherapy: From pipe dreams to (therapeutic) pipelines PNAS, October 5, 2004; 101(suppl_2): 14599 - 14606. [Abstract] [Full Text] [PDF]
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 Y. C. Q. Zang, J. Hong, V. M. Rivera, J. Killian, and J. Z. Zhang Human anti-idiotypic T cells induced by TCR peptides corresponding to a common CDR3 sequence motif in myelin basic protein-reactive T cells Int. Immunol., September 1, 2003; 15(9): 1073 - 1080. [Abstract] [Full Text] [PDF]
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 D. Winter, E. Fiebiger, P. Meraner, H. Auer, C. Brna, R. Strohal, F. Trautinger, R. Knobler, G. F. Fischer, G. Stingl, et al. Definition of TCR Epitopes for CTL-Mediated Attack of Cutaneous T Cell Lymphoma J. Immunol., September 1, 2003; 171(5): 2714 - 2724. [Abstract] [Full Text] [PDF]
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 R. H. McMahan, L. Watson, R. Meza-Romero, G. G. Burrows, D. N. Bourdette, and A. C. Buenafe Production, Characterization, and Immunogenicity of a Soluble Rat Single Chain T Cell Receptor Specific for an Encephalitogenic Peptide J. Biol. Chem., August 15, 2003; 278(33): 30961 - 30970. [Abstract] [Full Text] [PDF]
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J. Li, I. Goldstein, E. Glickman-Nir, H. Jiang, and L. Chess Induction of TCR V{beta}-Specific CD8+ CTLs by TCR V{beta}-Derived Peptides Bound to HLA-E J. Immunol., October 1, 2001; 167(7): 3800 - 3808. [Abstract] [Full Text] [PDF]
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J. Hong, Y. C. Q. Zang, M. V. Tejada-Simon, S. Li, V. M. Rivera, J. Killian, and J. Z. Zhang Reactivity and Regulatory Properties of Human Anti-Idiotypic Antibodies Induced by T Cell Vaccination J. Immunol., December 15, 2000; 165(12): 6858 - 6864. [Abstract] [Full Text] [PDF]
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