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[SANET-MG] immune reactions to transgenic proteins serious
http://www.i-sis.org.uk/TPTMMI.phpISIS Press Release 28/11/05
Immune Reactions to Transgenic Protein Serious
Independent Scientists Demand A Ban on GM Food & Feed while All GM Crops
The following memo and report were sent to international and national
regulators on behalf of the Independent Science Panel.
Please circulate widely, forward to your regulators and policy makers,
and the press.
From: Dr. Mae-Wan Ho, member of Independent Science Panel
(www.indsp.org), Director, Institute of Science in Society
To: (see list at the end)
I am writing on behalf of the Independent Science Panel (ISP)* to draw
your attention to new research findings on the safety of transgenic
proteins that need to be urgently addressed.
Specifically, immunological assessments carried out for the first time
on a transgenic protein revealed that post-translational processing
subsequent to gene transfer into an alien species introduced new
antigenicities that turned a previously harmless protein into a strong
immunogen. In addition, the transgenic protein promoted immune reactions
against multiple other proteins in the diet. The detailed findings are
reviewed in the report below.
As practically all the transgenic proteins involve cross-species gene
transfer, they will be subjected to different post-translational
processing, and hence they too, will have the potential to become
immunogenic. And yet, none of the transgenic proteins that have been
commercially approved has been tested. This omission is a most serious
public health issue.
We call on you to impose an immediate ban on all GM food and feed until
proper assessment on the immunogenicity of all the transgenic proteins
has been carried out.
*The ISP, launched 10 May 2003 at a public conference in London, UK,
consists of dozens of prominent scientists from 11 countries spanning
the disciplines of agroecology, agronomy, biomathematics, botany,
chemical medicine, ecology, epidemiology, histopathology, microbial
ecology, molecular genetics, nutritional biochemistry, physiology,
toxicology and virology (http://www.indsp.org/ISPMembers.php)
Transgenic Pea that Made Mice Ill
Raises serious safety concerns on transgenic proteins in general that
must be addressed while a ban on all GM food and feed is imposed. Dr.
Ten-year project down the drain but are the right lessons learned?
A ten-year project at CSIRO (Commonwealth Scientific and Industrial
Research Organization) in Canberra Australia bit the dust when peas
modified to resist insects caused inflammation in the lungs of mice .
The GM peas will be destroyed, said Gene Technology Regulator Sue Meeks.
The gene coding for the protein, a-amylase inhibitor-1 (aA1) in the
common bean (Phaseolus vulgaris L. cv. Tendergreen), was inserted into
pea (Pisum sativum L.) to make the pea-plants resistant to attack from
Dr. T.J. Higgins, deputy chief of CSIRO Plant Industry and co-author of
the scientific paper reporting the results remarked it is only the
second time in the world that a GM project has been abandoned after a
gene transfer from one crop to another, and that it demonstrated the
effectiveness of strict regulations on research into GM crops.
Greenpeace campaigner Jeremy Tager said: “It just shows the failure of
the science in relation to this gene product.”
Director of GeneEthics Network Bob Phelps referred to the project as a
“waste of public money” and highlights the growing concern worldwide
about the health impacts of all GM foods.
There are indeed important lessons to be learned from the scientific
findings , which raise serious safety concerns over transgenic
proteins in general.
Different processing of transgenic protein
The researchers found that the transgenic protein was processed
differently and provoked immune reactions not exhibited by the native
protein (see later).
Transgenic aA1 protein was compared with the non-transgenic protein on
Western blot, a technique that separates different forms of the protein
arising from post-translational processing. Previous studies showed that
the native polypeptide in bean is cleaved into two chains, a and b, both
of which are glycosylated (carbohydrate chains added), and with one or
more amino acids removed from the tail end. This results in major forms
of the a- and b-chains with molecular masses 11 646 Da and 17 319 Da
respectively, together with minor forms containing alternative
carbohydrate chains. The transgene in pea yielded a- and b-chains with
molecular masses in the11 000 – 18 000 Da region, but with a banding
pattern different from the native protein. More detailed comparisons on
mass spectroscopy showed that the transgenic a-chain was less heavily
glycosylated; and a form with two fewer mannose residues (11 322 Da) was
the dominant in transgenic pea, but the least abundant in bean. The
b-chain in the transgenic protein also showed a number of other bands
besides the major and minor forms present in the native protein.
Immune reactions to transgenic protein
Mice were given about 25mg of seed meal in suspension, containing
transgenic pea, nontransgenic pea, or bean, twice a week for 4 weeks.
Seven days after the final feeding, the mice were subcutaneously
injected in the footpad with the purified protein antigens: native or
transgenic aA1, and the swelling induced in the footpad assessed 24 h
In a second experiment, the mice were fed seed meal suspensions as
before, and seven and nine days after the final meal, purified
transgenic aA1 or buffered saline was introduced into the trachea, and
inflammation response was measured in the lungs 24 h later.
The results showed that mice fed on non-transgenic pea or bean showed no
inflammation response in the footpad or in the lungs, indicating normal
immune tolerance to common food.
Mice fed with transgenic pea, however, showed aA1-specific IgG
antibodies at two weeks, rising to significant levels after 4 weeks.
There was significant swelling of the footpad, or delayed type
hypersensitive (DTH) response, when purified aA1 was injected.
Similarly, introducing the antigens into the trachea gave an
inflammation response in the lungs.
As a control for the general effect of genetic modification, the footpad
challenge experiment was repeated with material from two other GM
plants, lupin expressing sunflower seed albumin (SSA) and chickpeas
expressing aA1. In contrast to transgenic pea, mice fed transgenic lupin
or transgenic chickpea did not give DTH response. This shows that the
response to transgenic pea was specific.
The peribronchial lymph nodes of the mice were tested for their response
to transgenic aA1. Only the lymph nodes of mice fed transgenic peas
responded by producing the inflammation cytokines (cell signalling
factors) when challenged with transgenic aA1.
Transgenic protein promotes reactions to other proteins
In order to test if the transgenic protein promotes immune reactions to
other proteins in the diet, mice were fed purified transgenic or native
aA1, or transgenic aA1 with or without ovalbumin three times a week for
2 weeks. One week following feeding, purified ovalbumin or buffered
saline were introduced into the trachea of the mice, and inflammation
response in the lungs was assessed as before.
Neither ovalbumin alone, nor ovalbumin in combination with native aA1
caused any inflammation response in the footpad or lungs when the mice
were challenged with ovalbumin. However, consumption of transgenic aA1
and ovalbumin together promoted a strong ovalbumin-specific antibody
response and predisposed the mice to inflammation when challenged with
ovalbumin in both the footpad and the trachea. This suggests that
transgenic aA1 did promote reactions to other proteins. In confirmation
of that, levels of antigen-specific IgG against other proteins such as
pea globulins, lectin, and vicilin-4 were also significantly higher in
the serum of mice fed transgenic pea than mice fed non-transgenic pea.
Wider implications on the safety of transgenic proteins that must be
The transgenic pea involved gene transfer between plant species, and is
generally thought to be much safer compared with the cross-kingdom gene
transfer – bacteria to plant – involved in the GM food crops that now
cover tens of millions of hectares worldwide.
A harmless bean protein expressed in transgenic pea caused inflammation
in mice, and research showed that the most likely reason is because the
protein is processed differently in peas. Such post-translational
processing of proteins is well known to be species-specific, and as
genetic modification almost invariably involves cross-species transfer
of proteins, one must expect transgenic proteins to differ structurally
from the native proteins as a matter of course. Are they also likely to
provoke immune reactions as a result?
It would not happen in every case, as the researchers have found that
neither transgenic lupin sunflower seed albumin, nor transgenic chickpea
aA1 gave the same results as transgenic pea aA1. But how frequently
could it happen?
“Currently, we do not know the frequency at which alterations in
structure and immunogenicity of transgenically expressed proteins occur
or whether this is unique to transgenically expressed aA1.” The
Furthermore, when consumed with other proteins, the transgenic pea
protein promoted immunological ‘cross-priming’ against those proteins,
so that the mice developed specific immunological reactions to them as
well. In other words, the transgenic protein can provoke generalised
immune response to multiple proteins in the diet, whether transgenic or not.
The previous instance of a GM project being abandoned was the transfer
of a Brazil nut allergen into soya , and it involved a known
allergen. The present case involves a protein that has all the
appearance of being harmless.
As yet, no other GM crop, especially those already out there in the
fields and in our food and feed, has been tested in this way. This must
now be done. Meanwhile, there must be a ban imposed on all GM food and feed.
1. “GM crops scrapped as mice made ill”, Selina Mitchell and Leigh
Dayton, The Australian, 18 November 2005.
Prescott VE, Campbell PM, Moore A, Mattes J, Rothenberg ME, Foster PS,
Higgins TJV and Hogan SP. Transgenic expression of bean a-amylase
inhibitor in peas results in altered structure and immunogenicity. J
Agricultural and Food Chemistry 2005, 53, 9023-30.
Nordlee JA, Taylor SL, Townsend JA, Thomas LA & Bush RK. Identification
of a brazil-nut allergen in transgenic soybeans. The New England Journal
of Medicine 1996, March14, 688-728.
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