Table Of ContentList of Contributors
Mahmoud Abu-Shakra Bradford C. Braden
Rheumatic Diseases Unit Center for Advanced Research in Biotechnology
Ben-Gurion University and Soroka Medical Centre University of Maryland Biotechnology Institute
Beer-Sheva, Israel Rockville, MD 20850, USA
Howard Amital Bernard R. Brodeur
Department of Medicine 'B' Unite de Recherche en Vaccinologie
Research Unit of Autoimmune Diseases Centre de Recherche du Centre Hospitaller de
Chaim Sheba Medical Center rUniversite Laval
Tel-Hashomer Sainte-Foy, Quebec, Canada
and Sackler Faculty of Medicine
Tel-Aviv University Dan Buskila
Tel-Aviv, Israel Rheumatic Diseases Unit
Ben-Gurion University and Soroka Medical Centre
Beer-Sheva, Israel
Ronit Bakimer
Department of Immunology
Michele Carbone
Weizmann Institute of Sciences
Department of Pathology
Rehovot, 76100, Israel
University of Chicago
Chicago, IL 60637, USA
Nenad Ban
Department of Biochemistry
Antonio Cassone
University of California
Laboratorio di Batteriologia e Micologia Medica
Riverside, CA 92521, USA
Istituto Superiore di Sanita
Rome, Italy
Agostino Bazzichi
Department of Biomedicine
Paul B. Chapman
University of Pisa
Melanoma Section
1-56127 Pisa, Italy
Clinical Immunology Service
Department of Medicine
Andrea Benden Memorial Sloan-Kettering Cancer Center
The Wistar Institute New York, NY 10021, USA
Philadelphia, PA 19104, USA
S. Conti
F. De Bernardis Istituto di Microbiologia
Laboratorio di Batteriologia e Micologia Medica Universita di Parma
Istituto Superiore di Sanita Parma, Italy
Rome, Italy
Elena Csernok
Malaya Bhattacharya-Chatterjee Department of Rheumatology
Markey Cancer Center University of Liibeck
University of Kentucky Rheumaklinik Bad Bramstedt
Lexington, KY 40536-0093, USA BadBramstedt, 24576, Germany
Constantin A. Bona Lilia Dakovska
Department of Microbiology Clinical Center of Endocrinology and
Mount Sinai School of Medicine Gerontology Medical Faculty
New York, NY 10029-6574, USA Sofia, Bulgaria
Vll
Franco Dammacco Franz-Josef Gaida
Department of Biomedical Sciences and Department of Clinical Chemistry
Human Oncology (D.I.MO) Medical Clinic
Section of Internal Medicine University Hospital Eppendorf
University of Bari Medical School D-20246 Hamburg, Germany
Bari, Italy
Carlo Garzelli
Howard Dang Department of Biomedicine
Audie L. Murphy Memorial Veterans Hospital University of Pisa
San Antonio, TX 7874, USA 1-56127 Pisa, Italy
YaronBarDayan M. Gerloni
Department of Medicine 'B' Istituto di Microbiologia
Research Unit of Autoimmune Diseases Universita di Parma
Chaim Sheba Medical Center Parma, Italy
Tel-Hashomer
M. Eric Gershwin
and Sackler Faculty of Medicine
Division of Rheumatology, Allergy and Clinical
Tel-Aviv University
Immunology
Tel-Aviv, Israel
University of California at Davis
TB 192, School of Medicine
Smruti Desai
Davis, CA 95616, USA
Department of Microbiology and Immunology
New York Medical College
Michael Grant
Valhalla, NY 10595, USA
Immunology Program
Faculty of Medicine
Hildegund C. J. Ertl
University of Newfoundland
The Wistar Institute
St. John's, Newfoundland, Canada
Philadelphia, PA 19104, USA
Neil S. Greenspan
Giuseppe Falcone
Department of Biological Science
Department of Biomedicine
Florida State University
University of Pisa
Tallahassee, FL 32308-3050, USA
1-56127 Pisa, Italy
and
Institute of Pathology
Jan Fagerberg
Case Western Reserve University
Department of Oncology (Radiumhemmet)
Cleveland, OH 44106-4943, USA
Karolinska Hospital
S-171 76 Stockhohn, Sweden Wolfgang L. Gross
Department of Rheumatology
Soldano Ferrone
University of Liibeck
Department of Microbiology and Immunology
Rheumaklinik Bad Bramstedt
New York Medical College
Bad Bramstedt, 24576, Germany
Valhalla, NY 10595, USA
Josee Hamel
Pnina Fishman Unite de Recherche en Vaccinologie
Felsenshtein Research Institute Centre de Recherche du Centre Hospitaller de
Beilinson Medical Campus rUniversite Laval
Petach Tiqvah, Israel Sainte-Foy, Quebec, Canada
Kenneth A. Foon
Markey Cancer Center David Harris
University of Kentucky Lankenau Hospital
Lexington, KY 40536-0093, USA Wynnewood, PA 19096, USA
vni
Dorothee Herlyn Ivan Kehayov
The Wistar Institute Department of Molecular Immunology
Philadelphia, PA 19104, USA Institute of Biology and Immunology of
Reproduction
Bulgarian Academy of Sciences
Jorma Hinkula
Sofia, Bulgaria
Microbiology and Tumorbiology Center
Karolinska Institute and Department of Virology Ronald C. Kennedy
Swedish Institute for Infectious Disease Control Department of Microbiology and Immunology
105 21 Stockholm, Sweden The University of Oklahoma
Health Sciences Center
Marina Incaprera Oklahoma City, OK 73190, USA
Department of Biomedicine
Heinz Kohler
University of Pisa
1-56127 Pisa, Italy Markey Cancer Center
University of Kentucky
Lexington, KY 40536-0093, USA
Franco Indiveri
Department of Internal Medicine (DI.M.I) Dieter Krebs
University of Genoa Medical School
Department of Gynecology and Obstetrics
Genoa, Italy
University of Bonn
Bonn, Germany
Lutz Jacob
The Wistar Institute Thomas J. Kunicki
Philadelphia, PA 19104, USA Roon Research Center for Arteriosclerosis and
Thrombosis
Division of Experimental Thrombosis and
Marc G. Jacquemin
Hemostasis
Katholieke Universiteit Leuven
Department of Molecular and Experimental
Center for Molecular and Vascular Biology
Medicine and the Department of Vascular
Campus Gasthuisberg, O & N
Biology
B-3000 Leuven, Belgium
Scripps Research Institute
La Jolla,CA 92037, USA
Simon Karpatkin
Department of Medicine Stanimir Kyurkchiev
New York University Medical School Department of Molecular Immunology
New York, NY 10016, USA Institute of Biology and Immunology of
Reproduction
Saoussen Karray Bulgarian Academy of Sciences
Departement d'lmmunologie Sofia, Bulgaria
Institut Pasteur
75015 Paris, France Ann Kari Lefvert
Immunological Research Laboratory and
Department of Medicine
Srini Kaveri
Karolinska Hospital, Karolinska Institute
INSERM U430 and Universite Pierre et Marie Curie
S-171 76 Stockholm, Sweden
Hopital Broussais
Paris, France
Patrick S.C. Leung
Division of Rheumatology, Allergy and
Michel D. Kazatchkine Clinical Immunology
INSERM U430 and Universite Pierre et Marie Curie University of California at Davis
Hopital Broussais TB 192, School of Medicine
Paris, France Davis, CA 95616, USA
IX
Michael Levi Abraham Mittelman
Microbiology and Tumorbiology Center Department of Medicine
Karolinska Institute and Department of Virology New York Medical College
Swedish Institute for Infectious Disease Control Valhalla, NY 10595, USA
105 21 Stockholm, Sweden
Marc Monestier
Weiping Li
Department of Microbiology and Immunology
The Wistar Institute
Temple University School of Medicine
Philadelphia, PA 19104, USA
Philadelphia, PA 19140, USA
Min Lin
Virology Section Sasha P. Moyes
Animal Diseases Research Institute Kennedy Institute of Rheumatology
Agriculture and Agri-Food Canada Hammersmith, London W6 7DW, UK
Nepean, Ontario K2H 8P9, Canada
Sybille Miiller
Alexander H. Lucas
Markey Cancer Center
Children's Hospital Oakland Research Institute
Department of Medicine
Oakland, CA 94611, USA
University of Kentucky
Lexington, KY, USA
Rizgar A. Mageed
Kennedy Institute of Rheumatology
Hammersmith, London W6 7DW, UK M.A. Nardi
Department of Medicine
Vanya Manolova New York University Medical School
Department of Molecular Immunology New York, NY 10016, USA
Institute of Biology and Immunology of
Reproduction Jacob B. Natvig
Bulgarian Academy of Sciences Institute of Immunology and Rheumatology
Sofia, Bulgaria The National Hospital
0172 Oslo, Norway
Haruhiko Maruyama
The Wistar Institute
Michael Neumaier
Philadelphia, PA 19104, USA
Department of Clinical Chemistry
Michael Mastrangelo Medical Clinic, University Hospital Eppendorf
Jefferson Medical College D-20246 Hamburg, Germany
Philadelphia, PA 19107, USA
Alfred Nisonoff
Alexander McPherson
Department of Biology
Department of Biochemistry
Rosenstiel Research Center
University of California
Brandeis University
Riverside, CA 92521, USA
Waltham, MA 02254-9110, USA
HakanMellstedt
Department of Oncology (Radiumhemmet) ElvyraJ.Noronha
Karolinska Hospital Department of Microbiology and Immunology
S-171 76 Stockholm, Sweden New York Medical College
Valhalla, NY 10595, USA
Ofer Merimsky
Department of Oncology Diane J. Nugent
Ichilov Hospital Children's Hospital of Orange County
Tel-Aviv 64239, Israel Orange, CA 92668, USA
Egbert Oosterwijk Jean-Marie R. Saint-Remy
814 Urological Research Laboratory Katholieke Universiteit Leuven
Department of Urology Center for Molecular and Vascular Biology
Academic Hospital Nijmegen Campus Gasthuisberg, O & N
6500 HB Nijmegen, The Netherlands B-3000 Leuven, Belgium
Harald Schlebusch
Harvey I. Pass
Department of Gynecology and Obstetrics
Thoracic Oncology Section
University of Bonn
Surgery Branch, NCI/NIH
Bonn, Germany
Bethesda, MD 20892, USA
Jan Schmolling
Federico Perosa Department of Gynecology and Obstetrics
Department of Biomedical Sciences and University of Bonn
Human Oncology (D.I.MO) Bonn, Germany
Section of Internal Medicine
John R. Schreiber
University of Bari Medical School
Department of Pediatrics
Bari, Italy
Case Western Reserve University School of Medicine
Chief, Division of Infectious Diseases
Dagmar Pieper
Rainbow Babies and Childrens Hospital
Department of Clinical Chemistry
Cleveland, OH 44106, USA
Medical Clinic, University Hospital Eppendorf
D-20246 Hamburg, Germany Marco Scudeletti
Department of Internal Medicine (DI.M.I)
Roberto J. Poljak University of Genoa Medical School
Center for Advanced Research in Biotechnology Genoa, Italy
University of Maryland Biotechnology Institute
Michael H. Shearer
Rockville, MD 20850, USA
Department of Microbiology and Immunology
The University of Oklahoma Health Sciences Center
L. Polonelli
Oklahoma City, OK 73190, USA
Istituto di Microbiologia
Universita di Parma Mark A. Sherman
Parma, Italy Division of Immunology and
Department of Molecular Graphics
Peter Ragnhammar Beckman Research Institute
Department of Oncology (Radiumhemmet) City of Hope National Cancer Center
Karolinska Hospital Duarte,CA91010,USA
S-171 76 Stockholm, Sweden
John E. Shively
Division of Immunology and
Jochen Reinsberg
Department of Molecular Graphics
Department of Gynecology and Obstetrics
Beckman Research Institute
University of Bonn
City of Hope National Cancer Center
Bonn, Germany
Duarte,CA 91010, USA
Kenneth H. Roux Yehuda Shoenfeld
Department of Biological Science Department of Medicine 'B'
Florida State University Research Unit of Autoimmune Diseases
Tallahassee, FL 32308-3050, USA Chaim Sheba Medical Center
and Tel-Hashomer
Institute of Pathology and Sackler Faculty of Medicine
Case Western Reserve University Tel-Aviv University
Cleveland, OH 44106-4943, USA Tel-Aviv, Israel
XI
Rajasekharan Somasundaram H. Uemura
The Wistar Institute Department of Urology
Philadelphia, PA 19104, USA Nara University
Nara, Japan
Sergio H. Spalter
Department of Immunology
Uwe Wagner
Institute of Biomedical Sciences
Department of Gynecology and Obstetrics
Sao Paulo, Brasil
University of Bonn
Bonn, Germany
Maria Stamenova
Department of Molecular Immunology
Institute of Biology and Immunology of BrittaWahren
Reproduction Microbiology and Tumorbiology Center
Bulgarian Academy of Sciences Karolinska Institute and Department of Virology
Sofia, Bulgaria Swedish Institute for Infectious Disease Control
105 21 Stockholm, Sweden
Eilleen S. Tackaberry
Life Sciences Division
Xinhui Wang
Bureau of Drug Research
Department of Microbiology and Immunology
Health Canada
New York Medical College
Ottawa, Ontario, Canada
Valhalla, NY 10595, USA
Norman Talal
Department of Medicine Ronald E.Ward
Division of Clinical Immunology Department of Molecular Immunology
University of Texas Health Science Center Roswell Park Cancer Institute
San Antonio, TX 78284-7874, USA Buffalo, NY 14263, USA
Yasmin Thanavala
Pierre Youinou
Department of Molecular Immunology
Laboratory of Immunology
Roswell Park Cancer Institute
Brest University Medical School
Buffalo, NY 14263, USA
Brest, France
Keith M. Thompson
Institute of Immunology and Rheumatology Jan Zaloudik
The National Hospital The Wistar Institute
0172 Oslo, Norway Philadelphia, PA 19104, USA
Yaron Tomer
En-Min Zhou
Division of Endocrinology and Metabolism
Virology Section
Department of Medicine
Animal Diseases Research Institute
Mount Sinai School of Medicine
Agriculture and Agri-Food Canada
New York, NY 10029, USA
Nepean, Ontario K2H 8P9, Canada
VasilkaTsvetkova
Department of Molecular Immunology MoncefZouali
Institute of Biology and Immunology of Reproduc Departement d'lmmunologie
tion Bulgarian Academy of Sciences Institut Pasteur
Sofia, Bulgaria 75015 Paris, France
xn
©1997 Elsevier Science B.V. All rights reserved.
Idiotypes in Medicine: Autoimmunity, Infection and Cancer
Y. Shoenfeld, R.C. Kennedy and S. Ferrone, editors.
ANTI-IDIOTYPES AS VACCINES:
THEORETICAL CONSIDERATIONS
Alfred Nisonoff
Department of Biology, Rosenstiel Research Center, Brandeis University, Waltham, MA 02254-9110, USA
The intention of this brief introductory chapter is to definition of idiotype are discussed in more detail
provide historical background on idiotypy and to discuss elsewhere (Nisonoff, 1995).
some of the issues involved in the use of anti-idiotypic As pointed out by Arthur Silverstein (1975), the
(anti-Id) antibodies as surrogate antigens, and in par concept of idiotypy dates back to the turn of the cen
ticular as vaccines. Various aspects of idiotypy have tury, when Paul Ehrlich and others predicted that anti
been reviewed elsewhere (Bona and Moran, 1985; bodies might be directed against the combining regions
Nisonoff, 1991; Greenspan, 1992; Kearney, 1993 of other antibodies (Himmelweit, 1956). At the time,
Shoenfeld et al., 1994; Thanavala and Pride, 1994 of course, nothing was known about the molecular
Kohler et al., 1995). The paper by Thanavala and Pride properties of an antibody. Ehrlich used the vague term
(1994) includes a list of over 50 investigations in which "side chain" to express the notion that particular chemi
anti-Id antibodies have been used to induce antibod cal structures define the antibody combining site and
ies against bacteria, viruses, parasites and tumor an that differences in side chains could account for dif
tigens. ferences in specificity. In addition to predicting that
The property of expressing an idiotype applies to the combining regions of two antibodies could inter
antibodies and T-cell receptors; for simplicity the act with one another, Ehrlich visualized the possibility
present discussion will be confined to antibodies. that the side chains of an anti-antibody (anti-anti-X)
Idiotypy has as its basis the diversity of antibodies, might resemble in structure the antigen (X), thus an
which is so great that an epitope present on an anti ticipating Jeme's later formulation of an "internal
body may be represented at very low frequency or be image" (see below). These early speculations seem
undetectable serologically in pooled normal im particularly remarkable since they were made in the
munoglobulins or antibodies of other specificities absence of information as to the actual structures
within the same species. Such an epitope is called involved.
an idiotope; the idiotype is the collection of idiotopes The modem era of research on idiotypy began in
on an antibody molecule. Antibodies reactive with 1955 with the work of Kunkel and his collaborators
idiotopes may remain in solution after thorough ad on human myeloma proteins (Slater et al., 1955). They
sorption of an anti-Id antiserum with nonspecific demonstrated that individual myeloma proteins possess
immunoglobulins. For reasons that are now obvious, antigenic determinants that could not be detected on
idiotopes are associated, entirely or in part, with the other such proteins or normal serum Ig. Idiotypy in
hypervariable regions of an antibody, discovered by antibodies was reported by Oudin and Michel (1963),
Wu and Kabat (1970). Although hypervariable re who were working with rabbit antisalmonella antibod
gions probably contribute to most or all idiotopes, ies, and by Kunkel's group in human antibodies to A
an idiotope may also include amino acids present in substance (Kunkel et al., 1963). The term "idiotype",
a framework region. Anti-idiotopes that bear a struc introduced by Oudin and Michel, was initially reserved
tural resemblance to the original, external antigen for determinants identified by a homologous antiserum
(see below) constitute only a small proportion of the (rabbit anti-rabbit in this instance). The term "indi
anti-Id antibody population. Issues relating to the vidual antigenic specificity" was used by Kunkel and
his collaborators, whose initial studies were carried identified, may become a useful tool and provide the
out with rabbit antihuman antibodies. The distinction basis for numerous publications (e.g., the phospho-
eventually disappeared from the literature and the term choline antigen in BALB/c mice).
"idiotype" is now used irrespective of the source of
the antiserum. Applications of CRIs
For a time it was thought that idiotypes were unique
to an individual animal as well as to antibodies of a Applications of CRIs include the following:
given specificity. Exceptions were observed starting An idiotype provides a phenotypic marker for the
in the late 1960s. Cold agglutinins from different in expression of particular V genes. For example, an early
dividuals were found to share idiotopes, although gen demonstration of the linkage of genes encoding idio
erally not complete idiotypes (Williams et al., 1968); type and heavy chain allotype indicated, in turn, the
different mice of the B ALB/c strain were found to pro linkage of VH and CH genes (Blomberg et al., 1972;
duce antibodies to pneumococcal C-carbohydrate that Pawlaketal., 1973).
expressed the same idiotype (Cohn et al., 1969); shared The presence in an individual patient of myeloma
idiotype in antibodies to streptococcal carbohydrates proteins of the IgM and IgG classes that shared idiotype
was noted in some members of a partially inbred fam provided early evidence that class switching can occur
ily of rabbits (Eichmann and Kindt, 1971); all indi while maintaining expression of the same VH gene
vidual A/J mice were found to produce antibodies to (Wang et al., 1970). This had been inferred earlier
the p-azobenzenearsonate hapten that shared idiotype through a demonstration of shared VH allotype in
(Kuettner et al., 1972). In the case of induced anti rabbit IgG and IgM (Todd and Inman, 1967). Identity
bodies shared idiotypy occurred in some but not all of of partial amino acid sequences of VH and VL regions
the relevant antibody population. of the IgG and IgM myeloma proteins that shared
Such recurrent or cross-reactive idiotypes (CRIs) idiotype provided convincing evidence for the reality
are now known to be fairly prevalent in inbred strains of the proposed class switching mechanism (Wang et
of mice and have proven useful in a variety of stud al, 1973).
ies (see below). In general, antibodies encoding CRIs Many studies of somatic mutations, and the rela
are encoded by germline genes that require few or tionship of specific mutations to affinity maturation
no somatic mutations to allow expression of the in antibodies have made use of CRIs; one can read
idiotype. A probable additional requirement is that ily screen for monoclonal antibodies expressing the
antibodies expressing the idiotype have a sufficiently CRI by serological analysis and thereby obtain a
high affinity so that receptors on B cells expressing collection of similar but nonidentical antibodies
the idiotype can compete successfully with other re belonging to the same genetic family. From their
ceptors specific for the same antigen but differing in sequences one can draw conclusions concerning the
idiotype. This combination — expression in the germ sequential accumulation of mutations that have taken
line and an affinity high enough to be competitive - place and their effects on affinity and on the ex
can explain the recurrence of an idiotype within an pression of particular idiotopes that comprise the
inbred strain, as well as intrastrain differences. (An idiotype.
tibodies to a given antigen may be associated with a In collaboration with the laboratory of Erik Seising
CRI in one strain but not another.) Despite the asso (Durdik et al., 1989) we used CRI expression as a
ciation with germ line genes antibodies expressing clonal marker to provide serological evidence for
a CRI exhibit heterogeneity (e.g., Lamoyi et al., interchromosomal H chain isotype switching in a
1980). Somatic mutations may result in a substan transgenic mouse. CRIs have also been used as clonal
tial increase in affinity while preserving some (usu markers for studies of B cell development and the fate
ally not all) of the idiotopes that comprise the idiotype of clones of B cells.
(Sharon, 1990). The term CRI should thus be con The existence of CRIs facilitated the demonstra
sidered as describing an idiotype family rather than tion that pretreatment with anti-Id antibodies can sup
an idiotype. press the subsequent appearance of the idiotype in
Whether a particular idiotype is cross-reactive response to challenge with the relevant antigen in vivo
within an inbred strain depends on the antigen and the (Hart et al, 1972; Strayer et al., 1975) or in vitro
strain. The actual prevalence of CRIs may be much (Cosenza and Kohler, 1972). A single anti-Id reagent
lower than the popular perception because a CRI, once can be used for experiments on suppression with vari-
ous members of an inbred strain. The suppression of 2. Interaction of the Anti-Id with Cellular Receptors
idiotype by anti-Id provided one of the foundations (Other than Antibodies) for the External Antigen
for Niels Jeme's idiotype network theory of immune
regulation (Jeme, 1974). There have been numerous reports of the interaction
of anti-Ids with cellular receptors for a variety of ex
ternal antigens (reviewed in Gaulton and Greene,
ANTI-ID ANTIBODIES EXPRESSING AN IN 1986). The earliest example was the work of Sege and
TERNAL IMAGE OF THE ANTIGEN Peterson (1978), who showed that anti-anti-insulin
antibodies could bind to insulin receptors on fat cells
Included in Jeme's network theory was the proposal of the rat and, in addition, induce some of the biologi
that the paratope of an anti-Id molecule (anti-anti- cal effects of insulin. This was the first strong experi
X) might in some instances bear a structural resem mental evidence supporting Jerne's concept of an
blance to an epitope on the external antigen, X. Jeme intemal image. The interaction with cellular receptors,
used the term "intemal image of the antigen" to de especially if the appropriate biological effects are me
scribe such a stmcture on the anti-Id antibody. Sub diated, is perhaps more convincing than the induction
sequent evidence supporting the validity of this of antibodies as evidence for structural relatedness of
concept led to the proposed use of anti-Id antibodies antigen and anti-Id. It seems unlikely, for example,
as vaccines (Nisonoff and Lamoyi, 1981; Roitt et al., that the insulin receptor would bear much structural
1981). resemblance to an anti-insulin antibody outside the in
sulin binding region.
CRITERIA FOR STRUCTURAL SIMILARITY 3. Competition of Antigen and Anti-Id for Binding
OF EPITOPES ON THE ANTIGEN (X) AND to Anti-X antibodies
ANTI-ID
This is a rather weak criterion because only partial
1. Capacity of the Anti-Id to Induce the Synthesis overlap may be needed for steric interference with
of Anti-X Antibodies binding.
This of course is a key element of structural relatedness 4. Comparison by X-ray Crystallography of the
because it is directly relevant to the capacity of the Interaction of Antigen and Anti-Id with the Same
anti-Id to act as a surrogate antigen in a vaccine. (The Antibody
question of T-cell stimulation will be considered later.)
However, the experiment is not convincing if, as some This is obviously the ultimate method for comparing
times reported, it is carried out in an animal that is structures on the antigen and anti-Id that make con
syngeneic with the donor of the anti-X antibodies used tact with the antibody. Results obtained by this tech
to generate the anti-Id. Within an inbred strain the same nique will be considered later.
idiotype may be present on many B cells. Such cells
may be activated to produce anti-X antibodies by an
anti-Id reagent directed to an epitope outside the DEGREE OF STRUCTURAL RELATEDNESS
antigen-binding region; in this case there would be no BETWEEN THE ANTIGEN AND ANTI-ID
requirement for a structural resemblance of the anti-
Id and the antigen. Such an anti-Id would, however, This question is of critical importance with respect to
probably fail to stimulate the formation of anti-X anti the potential use of anti-Id reagents as vaccines. The
bodies in a heterologous species; thus, a mouse anti- large number of instances in which anti-Id reagents
Id with these properties would not be useful as a have been successfully used to induce antibodies to a
vaccine in humans. Because some idiotypes are cross- variety of antigens, including pathogens (e.g.,
reactive even in different strains of mice, a mouse anti- Schoenfeld et al., 1994; Thanavala and Pride, 1994;
Id should be tested for its capacity to induce anti-X in Bona and Moran, 1985; Nisonoff, 1991), leaves no
another species. If, for example, it stimulates anti-X doubt that the appropriate B cells can frequently be
antibodies in rabbits it seems quite possible that it will stimulated by such immunization. However, the pre
also do so in humans. cise nature of the structural similarity between the
antigen and anti-Id is relevant to another question, antigen and antibody V regions were scanned for
namely, whether the anti-Id can activate antigen- maximum homology. Stretches of 8—25 amino acids
specific T cells. For many pathogens, as well as tumors, were generally compared.
T-cell responsiveness is known or predicted to be es Such studies clearly indicate that certain anti-Ids
sential for the prevention or cure of the disease. MHC share partial amino sequences with the antigen. In ad
restriction and T-cell recognition are based on linear dition, direct evidence for the induction by anti-Id of
amino acid sequences whereas antibody interactions cellular immunity specific for external antigens, in
involve the three-dimensional structure of the anti cluding pathogens and tumor antigens, has been re
gen. With respect to interaction with an antibody mol ported by a number of laboratories (Nepom et al., 1984;
ecule, even if the contact amino acids in the antigen Lee et al., 1985; Williams et al., 1989; Mellstedt et al.,
and anti-Id were identical this would provide no guar 1991; Velge-Roussel et al., 1991; Chatterjee et al.,
antee of appropriate similarity of linear sequences in 1993; Durrant et al., 1994; Herlyn et al., 1994; Yang
the epitopes responsible for T-cell stimulation. and Thanavala, 1995; Chakraborty et al, 1995; Durrant
The amount of published data relevant to the ques et al., 1995; Foon et al., 1995). T-cell involvement is
tion of structural resemblance is limited. Bruck et al. implied in all of these studies and a direct demonstra
(1986) demonstrated a significant resemblance be tion of T-cell activation was made in several instances.
tween amino acid sequences of a monoclonal anti-Id
and the antigen under investigation (type 3 reovirus
hemagglutinin). About half of a 16-amino acid se X-RAY CRYSTALLOGRAPHIC INVESTIGA
quence of the hemagglutinin shows homology with a TIONS OF MIMICRY OF ANTIGEN BY ANTI-ID
framework segment of the VH region. The remainder
of the 16-amino acid sequence is homologous to a VL X-ray crystallography is the definitive method for dem
sequence, mainly from the second CDR. It is of inter onstrating structural resemblance between an epitope
est that both the VL and VH peptide sequences showed of the antigen and anti-Id. A limitation is the large
cross reactivity with the hemagglutinin at the T-cell amount of effort required and the consequent paucity
level. In addition, studies with synthetic peptides of data. Nevertheless, interesting conclusions have
indicated that the regions of sequence similarity been derived by comparing the crystal structures of
corresponded with the site of attachment of the he Id—anti-Id and Id-antigen complexes. Each crystallo-
magglutinin to receptors on cells (Williams et al., graphic study made use of Fab or Fv fragments of a
1989). monoclonal antibody and its monoclonal anti-Id.
Another example comes from the laboratory of A crystallographic investigation by Garcia et al.
Fougereau (Mazza et al., 1985). The antigen used was (1992) demonstrates one mechanism by which mim
a random copolymer of glutamic acid, alanine and tyro icry may occur. With angiotensin II (All) as the exter
sine. The DH regions of several monoclonal anti-Ids nal antigen they generated Abl, Ab2 and Ab3. The
contained the sequences tyr-tyr-glu or glu-glu-tyr that mouse monoclonal Ab3 was found to bind All with
are closely related to immunodominant sequences of high affinity. Of particular interest was the observa
the antigen. tion that, in binding to Ab3, the All antigen adopted a
With thyrotropin as the antigen, Taub et al. (1992) conformation very similar to that of a loop in CDR3
detected sequences resembling those of the antigen in of the light chain of an (unrelated) myeloma protein;
the CDR regions of two anti-Id mAbs. Synthetic this might well account for the apparent mimicry of
polypeptides based on these sequences interacted with All by Ab2, i.e., the ability of Ab2 to induce anti-All.
thyrotropin receptors on rat thyroid cells and inhibited By X-ray analysis Bentley et al. (1990) found no
certain biological effects of thyrotropin in vitro. A evidence for structural similarity (mimicry) of the
moderate amount of sequence homology was also ob epitopes of the antigen, lysozyme, and the Fab of anti-
served between a heavy chain CDR sequence in a Id that interact with the same antibody. The authors
monoclonal anti-Id and a 23-amino acid sequence of claimed that the anti-Id expressed an internal image
a known epitope of the antigen, hepatitis B surface of the antigen according to serological criteria. How
antigen (Pride et al., 1992; see also Taub et al., 1989). ever, this conclusion was based on the induction of
It should be noted that the degree of sequence ho anti lysozyme antibodies, by immunization with anti-
mology observed in these investigations rarely ex Id (Ab2), in the same strain (BALB/c) that provided
ceeded 50% despite the fact that the sequences of the the Abl. As discussed above such an immunization
