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Biotecnologia Aplicada
Elfos Scientiae
ISSN: 0684-4551
Vol. 14, Num. 1, 1997, pp. 42
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Biotecnologia Aplicada 1997 Volume 14 No. 1, pp.42
WHAT DO GANGLIOSIDES SHOW US ABOUT IDIOTYPIC NETWORKS?
Rolando Perez, Ana Maria Vazquez, Eladio Iglesias, Amparo Macias, Josefa
Lombardero, Ernesto Moreno and Luis E Fernandez
Center of Molecular Immunology, Havana, Cuba.
Code Number:BA97006
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Introduction
Tumor-associated gangliosides are carbohydrate self-antigens very poorly
immunogenic (1). Many attempts have been made trying to improve their
immunogenicity by using T cell dependent vectors. However, specific active
immunotherapy with tumor-associated gangliosides has not been successful
enough in the clinical setting (2). We had the hypothesis that anti-
idiotypic MAbs could be used as T cell dependent antigen surrogates, as it
has been suggested by others (3).
Results and Discussion
Anti-Ganglioside Antibodies are most likely natural autoantibodies
Liposomes containing GM3 (NeuGc) elicited non boosteable, low titer, cross-
reactive anti-ganglioside IgM antibody responses in Balb/c mice. A unique
IgM MAb, P3, highly specific for N-glycolylated gangliosides was obtained
(4). P3 MAb heavy chain variable region had 94 % homology with an anti-PC
Ab, using the Q52 VH gene family (5), which is over-represented in neonatal
"natural" antibodies characterized by high degree of degenerate
"specificity" and high idiotypic connectivity (6). Two N-terminal addition
segments contribute to the H3 diversity of MAb P3. An Arginine pocket could
be defined on the P3 heavy chain variable region surface, into which the
negative carboxyl group of sialic acid might dock.
Anti-Ganglioside Antibodies Induce an Antigen-Independent Natural
Autoantibody response
This Ab1 antibody (P3), as other anti-ganglioside IgM antibodies coupled
with KLH, elicited a multispecific anti-ganglioside IgM antibody
serological responses (Ab1', titers 1/160 to 1/640) in syngeneic models.
Clonal analysis of this anti-anti-idiotypic responses by cell fusion
experiments showed the multispecificity of such Abs (reactivity also with
N-acetylated gangliosides). Ab1' responses had a maximun after two
immunization doses, while dropped with a third dose.
Anti-Ganglioside Antibodies Induce An Strong Anti-Idiotypic
Response
Anti-ganglioside IgM antibodies like P3 MAb coupled with KLH raised strong
IgG anti-idiotypic responses (Ab2, titers 1/10 000 to 1/50 000) in Balb/c
mice. No correlation between the IgM Ab1' and the IgG Ab2 titers was found,
but 98 % of Ab2 clones were specific for P3 MAb after the second dose, and
only 68 % after the third one. Moreover, most of these specific Ab2 clones
were able to block binding of P3 MAb to GM3 (NeuGc). The heavy chain
variable region sequence of one paratopic Ab2 contained 2 and 4 Asp
residues into H2 and H3 respectively, suggesting an "interaction mimicry"
of the sialic acid negative charge.
Anti-Idiotypic Antibodies Induce a "Natural" Autoantibody response to
Gangliosides
Half of the paratopic Ab2s tested so far in vivo, coupled with KLH
and combined with Freund incomplete adjuvant induced a low titer, not
boosteable, multispecific IgM antibody serological responses in syngeneic
and allogeneic models.
Concluding Remarks
In general, anti-Id MAbs to primary response anti-ganglioside MAbs do not
behave as T cell dependent antigen surrogates. To change the chemical
nature of the antigen surrogate seems to be not enough to break tolerance
to these self-antigens. Possible explanations according to the emerging
paradigms (7, 8) could be: 1) "internal image" according to the pre-immune
repertoire reference elicits a primary Ab response, 2) incomplete
"interaction mimicry" might induce epitope-shifting affecting antibody
specificity, 3) "structural restrictions" to idiotypic interactions might
prevent a mature anti-anti-idiotypic response, 4) "clonal dominance" of
natural autoantibodies might drive the inmune response hindering the clonal
expansion of emergent specific clones. According to our results anti-Id MAb
vaccines could be potentially useful for activating natural autoimmunity to
cancer cells.
References
1. Hakomori S. Adv Cancer Res 1989; 52:257-331.
2. Livingstone PO et al. Immunological Reviews 1995;145:147-166.
3. Irie RF et al. J Natl Cancer Inst 1990; 82:1757-1760.
4. Vazquez AM et al. Hybridoma 1995; 14:551-556.
5. Stenzel MP et al. J Immunol 1987; 139:1698-1703.
6. Holmberg D. Eur J Immunol 1987; 17:399-403.
7. Kohler H et al. Proc. 8th Intl Congr Immunol Budapest
1992.
8. Varela F, Coutinho A. Immunol Today 1991;12:159-165.l
Copyright 1997 Elfos Scientiae
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