IgG - IgG interactionS...

Mike Clark mrc7 at cam.ac.uk
Mon May 24 08:47:19 EST 1999

In article <Pine.A41.4.10.9905211153140.38516-100000 at dante24.u.washington.edu>,
F. Hayashi <URL:mailto:hayashi at u.washington.edu> wrote:
> On Fri, 21 May 1999, Mike Clark wrote:
>> In article
>> <Pine.A41.4.10.9905201917210.79322-100000 at dante21.u.washington.edu>,
>> One 'significance' of 'anti-iditoype antibodies' is that they can
>> seriously screw up the efficacy in use of therapeutic monoclonal
>> antibodies. Once a patient develops an anti-idiotype response it is
>> usually impossible to carry on with the therapy. 
> Can you give me a reference on such a case?  Just curious about the
> kinetics.

Ok, hope you don't mind if I select an example close to home!

The rat IgG2b monoclonal antibody CAMPATH-1G was found to be immunogenic in
most patients with anti-Fc, anti-Fab and anti-idiotype antibodies appearing
after about 10 days from start of therapy. The titre would generally reach
a maximum between 21-30days.
CAMPATH-1G was humanised to give CAMPATH-1H by CDR grafting. It was found
that CAMPATH-1H was much less immunogenic, as hoped and expected, with very
few antiglobulin responses being detected after a first course of
treatment. However some patients who received a repeat course of therapy
did start to make anti-idiotype responses.


CAMPATH-1H in rheumatoid arthritis--an intravenous dose-ranging
study. AUTHOR(S) Isaacs-JD; Manna-VK; Rapson-N; Bulpitt-KJ; Hazleman-BL;
Matteson-EL; St.-Clair-EW;Br-J-Rheumatol.1996 Mar; 35(3): 231-40.

'Forty-one patients with active and refractory rheumatoid arthritis(RA)
received a total of 100, 250 or 400 mg of CAMPATH-1H'...... 'Antiglobulin
responses developed in 9 of 31 patients tested'

And also....

Long-term remission of intractable systemic vasculitis with monoclonal
antibody therapy. AUTHOR(S) Lockwood-CM; Thiru-S; Isaacs-JD; Hale-G;
Waldmann-H  Lancet.1993 Jun 26; 341(8861): 1620-2.

'Substantial and sustained benefit was seen in three of the four patients,
although one of these three patients developed anti-idiotypic antibodies
that had to be removed by plasma exchange.'

> So, that's one 'significant' outcome of an anti-idiotype antibody.
> But Niels Jerne's idiotype cascade would predict that such an
> anti-idiotype antibody will elicit an anti-anti-idiotype antibody
> reaction, which (should? may?) have the same effect as the first
> therapeutic antibody.
> I don't buy the theory, but I was wondering if anybody has read any
> research on it?

I agree as you have stated it above the network idea has many problems. It
did for a long time stimulate a lot of research and after all science
should advance by disproof of a hypothesis.

Clearly any contemporary concept of an idotypic network also needs to take
into account our current understanding of positive and negative signalling
in B-cells.

Would an IgG antibody bound to FcgRIIB in fact switch off an anti-idiotypic
B-cell? If so would this mean that idiotypic networks are less likely for
IgG than for IgM?

How is an immunoglobulin processed and presented and by which cells?

Would the idiotype anti-idiotype recognition alter the processing as
demonstrated for other antigens (eg tetanus) as described by scientists
such as Colin Watts?

Would an antibody with complement component C3d bound to it provoke a
stronger anti-idiotypic response? (as for eg ovalbumin, as published by
Doug Fearon's lab) Thus would complement fixing antibodies be more likely
to provoke an anti-idiotype than non-complement fixing?

I think this last point is quite important. In experimental animal models
it is possible to tolerise with deaggragated 'foreign' IgG but not to the
same 'foreign' IgG given in aggregated form. Is this because the later
activates complement and binds to low affinity Fc receptors? Would the same
be true for naturally occurring immunglobulins ie would the 'self'
antibodies present in immune complexes be more likely to provoke an
anti-idiotype because they activate complement and bind to FcR?

Mike Clark,                        <URL:http://www.path.cam.ac.uk/~mrc7/>
 o/ \\    //            ||  ,_ o   M.R. Clark, PhD. Division of Immunology
<\__,\\  //   __o       || /  /\,  Cambridge University, Dept. Pathology
 ">    ||   _`\<,_    //  \\ \> |  Tennis Court Rd., Cambridge CB2 1QP
  `    ||  (_)/ (_)  //    \\ \_   Tel.+44 1223 333705  Fax.+44 1223 333875

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