From: Billi Goldberg <bigoldberg@igc.apc.org>
Subject: Antibody Masking of Epitopes
Note: Copyright 1992, Dan R. Greening. Non-commercial reproduction allowed.
Archive-Number: 6636
Organization: unspecified
Date: Tue, 15 Dec 92 13:11:24 PST

               ANTIBODY-DEPENDENT EPITOPE MASKING

The following is very interesting in light of the recent focus of the 
antibody (Th2) response in HIV+ individuals either with vaccines or 
other treatments. Is there a possibility that such antibody masking by 
blocking the Class I MHC (HLA-A,-B,-C) or other molecules prevent 
cytotoxic destruction of infected or abnormal cells? Is there a 
possibility that during the initial Th2 response to HIV on 
seroconversion that these antibodies mask infected cells preventing 
their clearance by the cell-mediated immune response? Does this have any 
connection to the increased neoplasms seen in HIV+?

I realize that this is the purest of speculations, but such articles as 
these continue to point out that, in some instances, the Th2 response 
may do more harm than good.

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Manson LA. Does antibody-dependent epitope masking permit progressive 
tumour growth in the face of cell-mediated cytotoxicity? Immunology 
Today, 1991 Oct, 12(10):352-5.                     

Abstract: It is not clear how immunogenic tumours can grow from small 
inocula in syngeneic hosts that mount both T-cell and B-cell responses. 
In this article Lionel Manson argues that antibody coats the tumour 
cells, protecting them from attack by cytotoxic lymphocytes, and thus 
permits the tumour to continue to grow and overwhelm the host. These 
observations may explain the paradox that an immunogenic tumour 
overwhelms the tumour-bearing host in the face of an ongoing anti-tumour 
immune response.

Page 352: The question that dominates tumour immunobiology is why and 
how a tumour can grow progressively and overwhelm a host despite the 
apparent immune response, both humoral and cell-mediated, that it 
triggers. Indeed, there has been a great deal of controversy as to 
whether autochthonous tumours are immunogenic at all. In recent years a 
consensus has begun to emerge that most, of not all, tumours are 
immunogenic, and that most, if not all, tumours are clonal. There is no 
consensus as to what constitutes immunogenicity, what defines a tumour-
specific antigen, what immune responses are seen in the tumour-bearing 
host and whether or not these responses are compatible with progressive 
tumour growth. The observations made in our laboratory suggest that, in 
some instances, antibody-dependent epitope masking may explain how 
immunogenic tumours grow progressively and overwhelm the host despite 
cell-mediated cytotoxic capacity.

Page 354: It is surprising that specific IgM, bound to the tumour cell 
in vivo, does not interfere with the growth of tumours. We have 
determined the growth rat of the L5178Y tumour both in vivo, where 
antibody is present, and in tissue culture, where it is not, and in both 
cases the population doubling time was about 11.5 h. It appears, 
therefore, that complement-induced lysis, antibody-dependent 
cytotoxicity (ADCC) and killing by macrophages do not take place in vivo 
during progressive tumour growth. This surprising conclusion is not 
novel, but was reached by Kaliss, who clearly demonstrated more than 30 
years ago that anti-tumour Ig will permit a tumour to grow from 
sublethal inocula in an allogeneic host and kill the host. He termed the 
phenomenon 'enhancement' in 1957 and called the Ig 'enhancing antibody.'

  The literature on immunological was reviewed in 1972 with the 
conclusion that specific Ig might play a role in allogeneic tissue graft 
enhancement. Ig has been observed bound to progressively-growing 
tumours, and this literature was reviewed most recently by Witz. To my  
knowledge, there is no adequate explanation for the lack of an effect of 
complement on Ig-coated cells in vivo: it is not clear whether the 
results are unique to tumour systems or whether they extend to any type 
of cell. Irrespective of the explanation, such observations should be 
kept in mind when the passive administration of anti-tumour antibody is 
proposed as a therapeutic modality. Klausner has recently observed that 
'naked' monoclonal antibody therapy 'would not do the trick' after 
reviewing the results of many such attempts.

  There has been much speculation on the role of immunological 
suppression during progressive tumour growth. Arguing against wholesale 
suppression, Goldstein found that normal immune responsiveness to a 
variety of immunogens could be demonstrated in tumour bearers as long as 
the tumour load was less that 10(8) cells per mouse, a level that is not 
known to induce any significant pathological changes in mice. Biddison 
and Palmer observed normal cell-mediated immune responses in the tumour-
bearing mouse, and we have observed an antibody response under the same 
in vivo conditions. It can be concluded, therefore, that non-antigen-
specific immunologic suppression is not displayed during the time when 
tumours grown from 103 to 108 cells.

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Manson LA. Novel tumor-specific antigen(s) response observed in a 
syngeneic lymphoma-bearing host. Cancer Detection and Prevention. 
.Supplement, 1987, 1:111-20. 
                                                                     
Abstract: Immunoglobulin (Ig) has been found to accumulate on P815Y (H-
2d) and L5178Y (H-2d) tumor cells during progressive growth in syngeneic 
host DBA/2 mice. Density of the accumulated Ig per cell increases as the 
tumor grows while the tumor cells become resistant to lysis by ascitic 
syngeneic cytotoxic cells. Tumor cells grown in vivo coated with this 
specific Ig no longer bind significant amounts of antibodies against H-
2D and H-2K antigens. The membrane-bound Ig reacts with a rabbit 
antimouse Fab and a rabbit antimouse IgM reagent, but it does not react 
with a rabbit antimouse IgG or IgA reagent. It binds specifically to 
tumor cell lines that are sensitive to the ascitic cytotoxic cells but 
not to resistant tumor cell lines. The membrane-bound Ig can be eluted 
from tumor cells with 3 M NaSCN or 0.2 M acetic acid. Binding studies 
indicate that this eluted Ig is not an anti-H-2D/K antibody, yet it 
immunoprecipitates H-2D/K antigens from NP40 lysates of P815Y cells. It 
is proposed that the Ig is directed against a tumor antigen that is 
physically associated with the H-2D/K antigens of the tumors.
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