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Perspectives in Cancer Research
Functional Idiotopes: Tumor Antigen–Directed Expression
of CD8+ T-Cell Epitopes Nested in Unique NH2-terminal
VH Sequence of Antiidiotypic Antibodies?
1
3
Kouichiro Kawano, Soldano Ferrone, and Constantin G. Ioannides
1,2
Departments of 1Gynecologic Oncology and 2Immunology, M.D. Anderson Cancer Center, Houston, Texas and
3
Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York
Abstract
Antiidiotypic antibodies have been and are being used for
cancer immunotherapy based on the rationale that Ab2
carrying an ‘‘internal image’’ of the corresponding tumor
antigen can induce tumor antigen–specific antibodies (i.e.,
Ab3 and inhibit tumor growth). Recent evidence indicates that
Ab2 also induces cellular responses by CD4+ and CD8+ T cells.
This finding has raised the question of where the short
peptides, which express CD8+ T-cell–defined epitopes, are
located and their relationship with the tumor antigen. We
found that two of the four known Ab2 associated with tumor
antigen, with known amino acid sequence, express unique
NH2-terminal VH sequences which precede the framework
regions. Both the unique and the shared NH2-terminal VH
sequences are nested MHC class I antigen–binding peptides.
These peptides were highly homologous with peptides from
corresponding tumor antigen (carcinoembryonic antigen,
CD55, and human high molecular weight melanoma–
associated antigen) but differed from the tumor antigen
peptides by the presence of the side chain known to mediate
stronger forces of interaction with other atoms. The presence
of candidate CTL epitopes in NH2-terminal VH of Ab2
homologous with tumor antigen may be important for the
development of novel immunotherapeutic strategies for
cancer. (Cancer Res 2005; 65(14): 6002-5)
The Idiotype Network Theory in the Context of
Cancer Immunotherapy
Active specific immunotherapy with well-defined moieties
represents an attractive approach to cancer therapy. A number of
immunogens are being tested in patients with various types of
malignant diseases. Among them are idiotype-specific antibodies
(i.e., antiidiotypic antibodies), which mimic tumor antigen. The use
of antiidiotypic antibodies as immunogens is based on the
rationale put forward by the idiotype network theory (1, 2).
According to this theory, an antigen induces an antibody
specifically recognizing a defined amino acid sequence/structural
motif unique to this antigen. This antibody is designated as Ab1. In
hematologic malignancies (myeloma, lymphoma, and leukemia)
the Ab1 bound on B-cell idiotype is a specific tumor antigen and,
due to mutations in VH regions, is also patient specific.
Because the antigen-binding amino acid sequence of Ab1 is
unique, Ab1 is seen as foreign by the immune system which has
Requests for reprints: Soldano Ferrone, Department of Immunology, Roswell Park
Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263. Phone: 716-845-8534; Fax:
716-845-7613; E-mail: [email protected].
I2005 American Association for Cancer Research.
Cancer Res 2005; 65: (14). July 15, 2005
produced it. As a consequence, the immunized host generates
another antibody, which specifically recognizes the antigen-binding
amino acid sequence of Ab1. This antibody is designated as Ab2 or
antiidiotypic antibody. Because only certain amino acid sequences
in antibody-binding regions differ between Ab1 and antibody of
other specificities present in the host, it is believed that Ab2
recognizes only the antigen-binding amino acid sequence on Ab1.
The antigen-binding amino acid sequence of Ab1 recognizes
several amino acids of the antigen and is recognized by Ab2. Due to
similarity between antigen and Ab1-binding amino acid sequence
of Ab2, it is generally believed that Ab2 carries the ‘‘internal image’’
of the antigen (1, 2). Based on this rationale, a number of
immunotherapy studies have used Ab2 as immunogens to elicit
tumor antigen–specific immunity (3).
The role of idiotype-specific immune responses in regulation of
tumor proliferation and metastasis is poorly understood. One
rationale for these studies is that Ab2 stimulates the immune
system to generate new antibodies to the internal image of the
antigen. These antibodies, generally defined as Ab3, will interact
with the inducing antigen on the tumor cell. The antigen-Ab3
interaction may mediate immune destruction of tumor cells and/or
inhibit a number of functions attributed to the tumor antigen. A
number of antibody found to be bound to tumor cells by the SEREX
approach (4) probably belong to both Ab1 and Ab3 categories.
There is also concern that Ab2 and Ab3 neutralize each other. A
second rationale for the use of Ab2 as an immunogen in
immunotherapy is that Ab2 can induce T cells interacting with
novel epitopes on Ab2 (3). The question of how this happens is
more complex than it initially seems. If the tumor antigen and the
Ab2 share linear amino acid sequence homology, then the resulting
T cells, as self-reactive T cells, should be tolerized or deleted.
However, if the homology is partial, Ab2-specific T cells which
recognize the tumor antigen, although with lower affinity than Ab2
peptides, may be activated. Most human tumor antigen peptides
recognized by CTL are weak and partial inducers of differentiation.
The differentiation of Ab2-specific T cells and their presence in
large numbers account for their ability to mediate an antitumor
response.
Structure of Antibody Variable Regions
The NH2-terminal regions of the heavy (H) and light (L) chains of
an antibody are implicated in antigen recognition (5, 6). Because
these regions recognize diverse amino acid sequences, and
maintain their folding, the first 120 to 140 NH2-terminal amino
acids define the variable region of the heavy (VH) and light (VL)
chains. Each contains three complementarity-determining regions
designated as CDR1, CDR2, and CDR3. These three regions are
more mutated compared with the intervening regions, which are
designated as framework regions. Differences in the antigen
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CD8+ Cell Recognized Tumor Antigen in Unique FR1
structure translate in amino acid differences in these regions.
These differences are more evident in the CDR3.
Early studies have proposed that only the complementaritydetermining regions of an antibody are involved in antigen
recognition. This model seemed to be correct for small molecules
(i.e., phenols or short sugars). Traditionally, the antibody epitopes
(B-cell idiotopes) forming internal images of the nominal antigen
are located in the CDR3. Epitopes recognized by CD4+ cells are also
present in CDR3 (7, 8). When an antibody recognizes a protein in
its native form, framework regions are likely to be involved in
antigen binding (5, 6). Considering that an antibody against a
protein has high affinity for its ligand, the specific recognition is
due to involvement of both framework region and CDR3. Then, the
idiotopes/internal images of the antigen should be present in
framework region and in CDR3 of Ab2. Because framework region 1
(FR1) is less diverse than the complementarity-determining region
but is the NH2-terminal sequence of VH, it is possible that unique
sequences are added to the FR1 to sense antigen. In the Ab2 they
will share homology with the antigen amino acid sequence.
Tumor Antigen and Ab2 Amino Acid Sequence
Comparison
There is no information available regarding homology between
tumor antigen amino acid sequences and unique NH2-terminal
V-region amino acid sequences of Ab2. We investigated whether
epitopes, which can be recognized by CD8+ T cells because they
bind MHC class I molecules, are present in the NH2-terminal V
regions preceding FR1. To date, there are only four published
amino acid sequences of Ab2/antiidiotypic antibody associated
with human tumor antigen with known amino acid sequence. Two
Ab2 have been generated and sequenced by one of us, and they
bear the internal image of distinct determinants of human high
molecular weight melanoma–associated antigen (HMW-MAA),
which is expressed in a high percentage of melanoma lesions (9).
These Ab2 are designated as MF11-30 and MK2-23, respectively
(10). The third Ab2, designated 105AD7, bears the internal image of
CD55 antigen. CD55 is widely expressed by colorectal carcinoma
cells (11, 12). The fourth Ab2, designated 3H1, bears the internal
image of carcinoembryonic antigen (CEA; refs. 5, 13).
First, we searched for unique VH peptides preceding FR1.
Then, utilizing proteomics programs available at http://
bimas.dcrt.nih.gov/molbio/hla_bind, we searched for HLA-A2
binding motifs in the unique VH peptides we had identified. To
identify homologous amino acid sequences in the tumor antigen,
the sequences of the identified unique VH peptides containing
HLA-A2 binding motifs were compared with the amino acid
sequences of the corresponding tumor antigen (HMW-MAA,
CD55, and CEA). Peptides from Ab2 CDR3, which lacked or
showed minimal homology with other immunoglobulin amino
acid sequences, were analyzed in parallel. We found that two of
the four Ab2 [i.e., monoclonal antibodies (mAb) MF11-30 and
105AD7] contain unique amino acid sequences located before
FR1. FR1 starts with a distinctive motif: EVQ, QVQ, EDQ in
position 17 to 19. These unique VH peptides encompass the first
18 and 24 amino acids of mAb MF11-30 and 105AD7 VH,
respectively (Fig. 1). The other two Ab2 (i.e., mAb MK2-23 and
3H1) do not contain unique VH peptides preceding FR1. The
unique VH peptides with HLA-A2 binding motifs from mAb
105AD7 and MF11-30 are shown in Table 1. Two of mAb 105AD7
peptides, designated as 105AD7 (7-16) and 105AD7 (2-10),
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Figure 1. Immunoglobulin VH region structure.
showed significant homology, 6/10 (60%) and 5/9 (55%),
respectively, with CD55 (14-23) and CD55 (373-381) amino acid
sequences (Table 2). Results for the pair HMW-MAA and mAb
MF11-30 have been published and are not repeated here (14).
mAb MK2-23 and 3H1 do not express unique NH2-terminal VH
amino acid sequences. However, two mAb MK2-23 peptides, MK223(12-20) and MK2-23(37-46), show significant homology with
HMW-MAA (1020-1028) and (825-834) amino acid sequences. mAb
MK2-23 amino acid sequence in CDR3 shows poor homology with
other VH amino acid sequences. It should be noted that the VH
CDR3 (100-117) amino acid sequence is 50% homologous with
HMW-MAA (690-706) amino acid sequence. The CDR3 amino acid
sequence resembles an MHC class II epitope due to the presence of
hydrophobic aliphatic and aromatic amino acids, which are known
to form MHC class II anchors. Peptides with this sequence may
activate CD4+ T cells as reported for CDR3 peptides from mAb 3H1.
Surprisingly, we found significant homology between the NH2terminal VH 3H1 peptide (12-20) and CEA isoform 1 (100-108). The
two nonamers, 3H1 (12-20) and CEA-1(100-108), are 55% homologous and can bind to HLA class I antigens.
The homology between tumor antigen and Ab2 amino acid
sequences is not random. It was not observed with amino acid
sequences from the immunoglobulin light chain. Also, VH of human
myelomas which contain unique FR1 (15) did not show such
extensive homology with HMW-MAA and CD55 as the one reported
here (data not shown). To summarize, two Ab2 carry unique NH2terminal VH sequences whereas two Ab2 do not. All four NH2terminal VH are more than 50% homologous with the inducer
tumor antigen. We have designated these Ab2/antiidiotypic
antibody NH2-terminal VH sequences as T-cell idiotopes because
they are homologous with somatic antigen.
Evaluation of Antigen-Ab2 Similarities in Energy Terms
The major structural differences between the tumor antigen
peptides and the corresponding T-cell idiotopes include (a)
introduction or removal of charged residues; (b) insertion of groups
which lead to misalignments; and (c) introduction of polar residues
which form H-bonds. Of the eight pairs of Ab2-tumor antigen shown
in Table 2, changes in charged residues are present in the pairs mAb
105AD7 (7-16)/CD55 (14-23), mAb MK2-23 (37-46)/HMW-MAA
(825-834), and mAb 3H1 (12-20)/CEA (100-108). Misalignments are
generated by insertion of (a) Ser7 in mAb 105AD7 (7-16), which
shifts the almost identical group (RVL) with the CD55 (14-23) group:
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Cancer Research
Table 1. Unique NH2-terminal amino acid sequences of VH antiidiotypic mAb 105AD7 and MF11-30
1
mAb MF11-30
mAb 105AD7
1
K M L L V L L Y S K L S S Q C A E D Q T A V H L24
D T L C Y T L L L T I P S R V L S18-Q V T L
NOTE: Candidate CTL epitopes are shown in bold. The mAb 105AD7 amino acid sequence after amino acid 18 is added to show the complete amino
acid sequence of the second CTL epitope.
RLL; (b) Ser6 in mAb MD2-23, which also shifts the almost identical
group: RKL with the HMW-MAA group RRL; and (c) Asp6 in mAb
MK2-23, which also shifts the almost identical group KKG with the
group RKG in HMW-MAA (825-833). The Ab2-tumor antigen
peptide pairs which lack changes in charged residues show changes
in polar residues such as Ser7!Gly7 (pair 1), Thr5!Phe5 (pair 2), as
well as Cys3!Val3 (pair 3).
These findings raise important questions regarding the effects of
changes in VH amino acid sequence on T-cell activation. If a selfantigen such as CD55 fails to induce CTL specific for the peptide
CD55 (14-23), this may be due to T-cell deletion or to ignorance
because of repulsion of T-cell receptor by negative charges on side
chains. In energy terms, electrostatic forces are the strongest
between atoms. In this case, stimulation with peptide 105AD7
(7-16) may activate cross-reactive CD8+ T cells. Similarly, if the CEA
(100-108) is not sufficiently activating CD8+ T cells, the peptide 3H1
may be a stronger immunogen because Lys4 can induce 10-fold
stronger electrostatic forces than Tyr4 (see pair 8, Table 2).
Generation of tumor antigen–specific CTL should be enhanced if
proinflammatory/inflammatory cytokines are administered. In the
clinical trial with mAb MF11-30(3-11), Bacillus Calmette-Guerin was
used as an adjuvant (14). Therefore, Ab2 can be used to activate
humoral or cellular responses to cancer according to disease
(i.e., myeloma/lymphoma or solid tumors).
Proposed Model
The reasons for the presence of unique NH2-terminal VH
sequences with high frequency in Ab2 (anti-idiotype) are unclear.
During the class switch to immunoglobulin G (IgG), novel VH
families are used by antibody to increase the binding affinity for the
antigen (16). It is unknown how these VH families are selected and
whether unique NH2-terminal VH inserts are associated with a
particular VH gene. Based on alignment with IMGT program (http://
imgt.cines.fr), the VH of mAb MF11-30 and 105AD7 belong to VH
families Q52 and IgG VHII, respectively. The first 23 amino acids of
mAb MF11-30 VH are absent from all other IgGs. The first six NH2terminal amino acids of mAb 105-AD7 VH are absent from most
IgGs. Compared with the few more homologous IgG or hypothetical
proteins, the following 11 amino acids had one deletion, which
resulted in a misalignment plus at least four to five nonconservative
changes. The only partial match for mAb 105AD7H/DTLCYT was
found in a rearranged VH pseudogene (DILCST) that has deleted the
CDR2 (17). One possibility is that changes are selected by Ab2 to
enhance contact with antigen. Another possibility is that unique
NH2-terminal VH inserts may have been selected based on the Ab2
CDR3 amino acid sequence. If this is the case, CDR3 determines
whether the Ab2 will induce antigen-specific CD8+ T cells. CD8+ Tcell responses induced by antiidiotypic antibodies in myelomas have
been recently observed (18). Mutations consisted in introduction of
Table 2. Amino acid sequence homology between VH of Ab2 and tumor antigens HMW-MAA, CD55, and CEA
c
Pair
Source
Position
Sequence*
Homology
HLA association
1
MF11-30
HMW-MAA
MF11-30
HMW-MAA
105AD7
CD55
105AD7
CD55
105AD7
CD55
MK2-23
HMW-MAA
MK2-23
HMW-MAA
3H1
CEA
3
74
16
303
2
373
7
14
14
20
12
1,020
37
825
12
100
L LVLLY SKL
LLQLYSGRL
AEDQTAVHL
VEDTFCFHV
TLCYTLLLT
TLV TMG LLT
LLLTIPSRVL
LLGE LPRLLL
RVLSQVTL
RLLLLVLL
V Q P G G S RK L
VAR GGRRLL
VR QAPE KKGL
VVQAPRKGNL
ELVKPGASL
ETIYPNASL
5/9
A201, A205, A24, B2705
5/9
B60, B61, B2705, B4403
5/9
A201, B2705
6/10
A201, B62, B2705, B5102
6/8
A201, A205, B2705
5/9
A24, B7, B2705
6/10
A205, A24, B2705, B3902
5/9
A24, B14, B62, B3901
2
3
4
5
6
7
8
NOTE: Amino acid sequence similarity was determined using the Expasy SIM alignment program.
*Identical or very similar residues are in bold. Substituted and inserted residues in Ab2 are enlarged.
cThe HLA allospecificity bound by both Ab2 and tumor antigen peptide is indicated. The HLA allospecificity bound with the highest affinity is
underlined. Determinations were made using the HLA peptide motif search program BIMAS.
Cancer Res 2005; 65: (14). July 15, 2005
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CD8+ Cell Recognized Tumor Antigen in Unique FR1
polar and charged residues. This amino acid sequence was followed
by conserved FR1. Naturally occurring CTL precursors with
specificity for Ab2 as well as suppressor T cells induced by Ab2
have been reported (19, 20). Is Ab2 directing the response to tumor
antigen by determining whether CD8+ cells will be activated or not?
Further studies determining the affinity of Ab2/antiidiotypic
antibody peptide and tumor Ag for TCR of CD8+ T cells will be
useful to clarify this issue.
The functional T-cell idiotope approach to tumor immunity
suggests that CTL epitopes are generated from the nascent VH
chains of Ab2 and are presented by B cells directly to Tcells. A unique
amino acid sequence is formed by joining three to five amino acids of
the leader with the new insert and the first amino acids of the FR1.
Endogenous peptides of this sequence can be presented by various
MHC molecules. A recent report on activation of CD4+T cells by
mutated FR1 supports this hypothesis (21). This mechanism of
antigen generation and presentation differs from the mechanism of
generation of novel candidate CTL epitopes by modification of HLAA2 anchor residues in FR1 of Ab1 reported in myelomas (22, 23). The
functional T-cell idiotope approach to tumor antigen discovery
differs from the phage-display antibody library and SEREX
approaches (i.e., refs. 24, 25), because it searches for CTL epitopes
in antiidiotypic antibody/Ab2. The phage display and SEREX identify
tumor antigen recognized by Ab1 and/or Ab3 but not the sequence
of the CTL epitope of the tumor antigen nested in Ab2.
Ab2 which induces CD8+ T-cell responses should lead to
discovery of novel tumor antigen. Isolated B cells with blocked
Fc receptors can be identified after reaction with the IgG fraction of
the same patient serum. Isolated mRNA could be amplified with
IgG primers and sequenced. The unique NH2-terminal VH sequence
References
1. Jerne NK, Roland J, Cazenave PA. Recurrent idiotopes
and internal images. EMBO J 1982;1:243–7.
2. Jerne NK. Idiotypic networks and other preconceived
ideas. Immunol Rev 1984;79:5–24.
3. Pride MW, Shuey S, Grillo-Lopez A, et al. Enhancement
of cell-mediated immunity in melanoma patients
immunized with murine anti-idiotypic monoclonal
antibodies (MELIMMUNE) that mimic the high molecular weight proteoglycan antigen. Clin Cancer Res 1998;
4:2363–70.
4. Chen YT, Scanlan MJ, Sahin U, et al. A testicular
antigen aberrantly expressed in human cancers detected
by autologous antibody screening. Proc Natl Acad Sci
U S A 1997;94:1914–8.
5. Li Y, Spellerberg MB, Stevenson FK, Capra JD, Potter
KN. The I binding specificity of human VH 4–34 (VH
4–21) encoded antibodies is determined by both VH
framework region 1 and complementarity determining
region 3. J Mol Biol 1996;256:577–89.
6. Potter KN, Li Y, Mageed RA, Jefferis R, Capra JD. Antiidiotypic antibody D12 and superantigen SPA both
interact with human VH3-encoded antibodies on the
external face of the heavy chain involving FR1, CDR2
and FR3. Mol Immunol 1998;35:1179–87.
7. Chatterjee SK, Tripathi PK, Chakraborty M, et al.
Molecular mimicry of carcinoembryonic antigen by
peptides derived from the structure of an anti-idiotype
antibody. Cancer Res 1998;58:1217–24.
8. Tripathi PK, Qin H, Deng S, et al. Antigen mimicry by
an anti-idiotypic antibody single chain variable fragment. Mol Immunol 1998;35:853–63.
9. Campoli M, Chang CC, Kageshita T, Wang X,
McCarthy JB, Ferrone S. Human high molecular
weight-melanoma-associated antigen (HMW-MAA): A
www.aacrjournals.org
of Ab2 could be compared with those of tumor proteins to identify
candidate CTL epitopes. If the peptide corresponding to the T-cell
idiotope activates, and expands CTLs, which recognize tumor cells,
it will indicate that idiotope-specific CTLs are functional The
presence of CTL epitopes in the T-cell idiotopes raise the possibility
of using peptides corresponding to these idiotopes and even Ab2 to
elicit effector CTL targeting the corresponding tumor.
In conclusion, we found significant similarities (50-60%) between
candidate CTL epitopes mapped to a new NH2-terminal sequence
of VH of Ab2/antiidiotypic antibody and the tumor antigen which
induced Ab1. The differences between Ab2 and tumor antigen
consisted mainly in charged residues in the former. Unique NH2terminal VH sequences seemed to be generated either by nucleotide
insertion or from a highly mutated germ line preceding the
constant amino acid sequence of FR1. Ab2 peptides homologous
with tumor antigen peptides may be stronger immunogens than
the tumor antigen peptides for induction of CTL recognizing
tumors expressing these antigen. Ongoing studies in our laboratory
aim to address whether CD8+ cell idiotypes are immunogenic and
induce protection from tumor growth in transgenic animals.
Acknowledgments
Received 9/20/2004; revised 3/9/2005; accepted 4/20/2005.
Grant support: Public Health Service grants P01 CA89480 and R01 CA105500
awarded by the National Cancer Institute, Department of Health and Human Services,
the Harry J. Lloyd Charitable Trust, DOD grant 1-01-0299, the Keck Foundation and
Grant No. P50 CA93459 (MDACC-melanoma SPORE). Its contents do not necessarily
reflect the views of the NIH.
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.
melanoma cell surface chondroitin sulfate proteoglycan
(MSCP) with biological and clinical significance. Crit
Rev Immunol 2004;24:267–96.
10. Kusama M, Kageshita T, Chen ZJ, Ferrone S.
Characterization of syngeneic antiidiotypic monoclonal
antibodies to murine anti-human high molecular
weight-melanoma associated antigen monoclonal antibodies. J Immunol 1989;143:3844–52.
11. Medof ME, Lublin DM, Holers VM, et al. Cloning
and characterization of cDNAs encoding the complete sequence of decay-accelerating factor of human
complement. Proc Natl Acad Sci U S A 1987;84:
2007–11.
12. Spendlove L, Li L, Potter V, Christiansen D, Loveland
BE, Durrant LG. A therapeutic human anti-idiotypic
antibody mimics CD55 in three distinct regions. Eur J
Immunol 2000;30:2944–53.
13. Beauchemin N, Benchimol S, Cournoyer D, Fuks A,
Stanners CP. Isolation and characterization of fulllength functional cDNA clones for human carcinoembryonic antigen. Mol Cell Biol 1987;7:3221–30.
14. Murray JL, Gillogly M, Kawano K, et al. Fine
specificity of high molecular weight melanoma–
associated antigen-specific cytotoxic T lymphocytes
elicited by anti-idiotypic monoclonal antibodies
in patients with melanoma. Cancer Res 2004;64:
5481–8.
15. Trojan A, Schultze JL, Witzens M, et al. Immunoglobulin framework-derived peptides function as cytotoxic T-cell epitopes commonly expressed in B-cell
malignancies. Nat Med 2000;6:667–72.
16. Itoh K, Meffre E, Albesiano E, et al. Immunoglobulin
heavy chain variable region gene replacement as a
mechanism for receptor revision in rheumatoid
arthritis synovial tissue B lymphocytes. J Exp Med 2000;
192:1151–64.
6005
17. Takahashi N, Noma T, Honjo T. Rearranged
immunoglobulin heavy chain variable region (VH)
pseudogene that deletes the second complementaritydetermining region. Proc Natl Acad Sci U S A 1984;
81:5194–8.
18. Wen YJ, Barlogie B, Yi Q. Idiotype-specific cytotoxic T
lymphocytes in multiple myeloma: evidence for their
capacity to lyse autologous primary tumor cells. Blood
2001;97:1750–5.
19. Monroe JG, Gurish M, Dambrauskas J, Slaoui M,
Lowy A, Greene MI. Genetic and biological characterization of a T suppressor cell induced by anti-idiotypic
antibody. J Immunol 1985;135:1589–97.
20. Dohi Y, Yamada K, Ohno N, et al. Naturally occurring
cytotoxic T lymphocyte precursors with specificity for
an Ig idiotype. J Immunol 1988;141:3804–9.
21. Zhang X, Smith DS, Guth A, Wysocki LJ. A receptor
presentation hypothesis for T cell help that recruits
autoreactive B cells. J Immunol 2001;166:1562–71.
22. Harig S, Witzens M, Krackhardt AM, et al. Induction
of cytotoxic T-cell responses against immunoglobulin V
region-derived peptides modified at human leukocyte
antigen-A2 binding residues. Blood 2001;98:2999–3005.
23. Gricks CS, Gribben JG. Cytotoxic T cell responses
against immunoglobulin in malignant and normal B
cells: implications for tumor immunity and autoimmunity. Curr Pharm Des 2003;9:1889–903.
24. Linnemann T, Wiesmuller KH, Gellrich S, Kaltoft K,
Sterry W, Walden P. A T-cell epitope determined with
random peptide libraries and combinatorial peptide
chemistry stimulates T cells specific for cutaneous T-cell
lymphoma. Ann Oncol Suppl 2000;1:95–9.
25. Mischo A, Wadle A, Watzig K, et al. Recombinant
antigen expression on yeast surface (RAYS) for the
detection of serological immune responses in cancer
patients. Cancer Immun 2003;27:3–5.
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Downloaded from cancerres.aacrjournals.org on June 17, 2017. © 2005 American Association for Cancer
Research.
Functional Idiotopes: Tumor Antigen−Directed Expression of
CD8 + T-Cell Epitopes Nested in Unique NH2-terminal VH
Sequence of Antiidiotypic Antibodies?
Kouichiro Kawano, Soldano Ferrone and Constantin G. Ioannides
Cancer Res 2005;65:6001-6004.
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