Table Of ContentImmune
Surveillance
Edited by
Richard T. Smith University of Florida
School of Medicine
and
Maurice Landy National Institute of
Allergy and
Infectious Diseases
Proceedings of an International Conference
Held at Brook Lodge
Augusta, Michigan
May 11 -13,1970
Academic Press
New York · London — 1970
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C O N F E R E ES
William H. Adler, University of Florida, Gainesville, Florida
Peter Alexander, Chester Beatty Research Institute, Sutton, Surrey, England
Anthony C. Allison, National Institute for Medical Research, London,
England
Barry R. Bloom, Albert Einstein College of Medicine, Bronx, New York
Edward A. Boyse, Sloan-Kettering Institute, New York, New York
Ruggero Ceppellini, University of Turin, Turin, Italy
Melvin Cohn, Salk Institute, La Jolla, California
Vittorio Defendi, The Wistar Institute, Philadelphia, Pennsylvania
Richard W. Button, University of California, La Jolla, California
James Ebert, Carnegie Institution of Washington, Baltimore, Maryland
Robert A. Good, University of Minnesota, Minneapolis, Minnesota
Geoffrey Haughton, University of North Carolina Chapel Hill, North
Carolina
Karl-Erik Hellström, University of Washington, Seattle, Washington
Richard Huemer, Veterans Administration Hospital, Sepulveda, California
Niels K. Jerne, Basel Institute for Immunology, Basel, Switzerland
David Keast, University of Western Australia, Perth, Australia
Maurice Landy, National Institute of Allergy and Infectious Diseases,
Bethesda, Maryland
H. Sherwood Lawrence, New York University, New York, New York
Jean Lindenmann, University of Zurich, Zurich, Switzerland
Charles F. McKhann, University of Minnesota, Minneapolis, Minnesota
ix
CONFEREES
N. Avrion Mitchison, National Institute for Medical Research, London,
England
Goran Möller, Karolinska Institute, Stockholm, Sweden
Richmond T. Prehn, The Institute for Cancer Research, Philadelphia,
Pennsylvania
Ivan M. Roitt, The Middlesex Hospital Medical School, London, England
Robert S. Schwartz, New England Medical Center, Boston, Massachusetts
Morten Simonsen, University of Copenhagen, Copenhagen, Denmark
Richard T. Smith, University of Florida, Gainesville, Florida
Osias Stutman, University of Minnesota, Minneapolis, Minnesota
Lewis Thomas, Yale University, New Haven, Connecticut
Roy L. Walford, University of California, Los Angeles, California
Darcy B. Wilson, University of Pennsylvania, Philadelphia, Pennsylvania
χ
PREFACE
The proposition that malignant tumors encounter in the host some measure
of resistance is an old and venerable one. However, it was not until 1957 that
this idea was given scientific validation by Prehn and Main when they dem-
onstrated unequivocally that experimental tumors evoke in the host immu-
nologically specific resistance via the expression of unique neoantigens. This
epochal discovery provided the firm foundation of and the impetus for the
present renaissance of tumor immunology. The subsequent application of
this principle to the autochthonous host by Klein and colleagues extended
its relevance to cancer as it occurs in humans. A decade of highly energetic
amplification of these principles in laboratories all over the world has yielded
an astonishing depth of understanding of the immunologic aspects of host-
tumor interactions, and has led to appreciation that the occurrence of tumor-
specific antigenicity is essentially universal. Both humoral and cell-mediated
expression of the immune response specifically directed toward these tumor-
in vitro
membrane neoantigens are now established, being demonstrable both
and in vivo.
From this decade of accelerating experimental efforts stimulated by these
original discoveries, four essentially unresolved central issues have emerged:
( 1 ) the cellular mechanisms governing the generation, production, and expres-
sion of tumor-specific transplantation antigens in the cell membrane remain
unclear; (2) the paradox implicit in the fact that tumor-bearing hosts have
demonstrable evidence of both cellular and antibody-mediated immunity
specific for their own tumors, even as the tumor itself continues to enjoy un-
retarded growth oblivious of this immunologic army; (3) much uncertainty
remains regarding the actual mechanisms for generation of the capacity to
sort out and perceive on membranes structures including the antigens on
tumor cells which are to be attacked and at the same time distinguish these
from similarly presented structures which are self and therefore to be ignored;
(4) there is an implicit but as yet not validated role for the lymphoreticular
system in surveillance — the early identification of and immunologically
mediated disposal not only of newly transformed cells but also cells which
are senescent, those that have inappropriate embryonic characteristics, and
xi
PREFACE
those with intracellular parasites which signal their presence through a mem-
brane change.
This volume is the tangible expression of the editors' conviction that the time
was appropriate for review and assessment of the basic surveillance concept
in the context of the Brook Lodge Immunology Conferences. However, as the
reader will readily discern, each of these central issues that currently dominate
tumor immunology was also extensively explored by the conferees, and this
deployment of efforts is reflected in the organization of this conference
volume.
The first section deals largely with the origin and expression of membrane
antigens, and considers this area in the light of a new concept of membrane
organization developed by Boyse. The second and third analyze, sort out, and
evaluate alternatives for the requisite recognition and destruction mechanisms
in the light of present knowledge of cell cooperation and requirements for
immune recognition. The fourth presents a fruitful attempt to resolve the
in vitro
paradox of thriving tumors in the presence of demonstrable host im-
munity. The fifth is based on the first presentation and critique of Jerne's
comprehensive theory to account for the generation of immunologic diversity.
The final section is devoted to the surveillance hypothesis and emerges as a
weighted evaluation of the evidence.
Central to the theme of surveillance is the recognition that the life span of
the mammalian host is spent in an environment replete with mutagenic
agents and situations. It is, however, evident that despite the major pressures
directed toward transformation represented by normal cell mutation, chem-
ical carcinogens, oncogenic viruses, and still other mutagenic situations, the
great majority of mammals complete most of their life span quite free of
overt malignancy. This happy situation can hardly be fortuitous; it can more
logically be interpreted as an expression of a superbly functioning host system
of surveillance. It is thus of paramount importance to understand the genetic
and immunologic factors that may be compromised and circumvented and
thus render impotent what is normally an extraordinarily efficient and effec-
tive mechanism. This mechanism has the capacity of selecting out and elimi-
nating all cells with surface membrane characteristics deviating significantly
from self. To obtain incontrovertible evidence for the surveillance of host
cell alterations is apparently not possible at present. However, as an operation-
ally useful guiding concept for future research in this fascinating area of cell
biology, it appears to sustain its promise after searching criticism.
xii
PREFACE
Both the conference and this volume have amply fulfilled our high expecta-
tions, for which we are greatly indebted to several people who played a key
role behind the scenes: Mr. Eugene Wallach whose now immunologically
oriented stenotypy expertise provided an accurate transcript of the volatile
discussions with their exotic terminology ; our secretarial assistants Mrs. Penny
Marquette and Mrs. Evelyn Rosenstein whose devotion to this task and effec-
tiveness in coping with the numerous, varied arrangements and all stages of
the editorial process did so much to assure this final product; Dr. Norman
Marshall and the Upjohn Research Organization for their warm cooperation
in arranging for the continued association of Brook Lodge with these Im-
munology Conferences.
Richard T. Smith
Maurice Landy
xiii
INTRODUCTORY NOTE
As a hybrid discipline, immunology has had distinctive problems in effecting
the transition from descriptive phenomenology to comprehension of underly-
ing mechanisms. There nonetheless continues to be impressive growth in
understanding and inexorable movement toward integrating data and findings
into basic operational concepts. Also developing in a parallel fashion is per-
ception of the way in which the multifaceted capability of the immune ap-
paratus evolved and its probable role in the evolution of the vertebrates to
their present state. The concept of immune surveillance, so central to this
theme, and the immune mechanism as we presently know it were, therefore,
logical topics for the third of this series of conferences organized by the
National Institute of Allergy and Infectious Diseases.
The small multidisciplinary conference of specialists is becoming more widely
accepted because of its exceptional informational benefits. On the basis of the
experience gained thus far in organizing three Brook Lodge conferences it may
be appropriate to mention some of the factors that have guided the plans for
and the conduct of these meetings, so useful for conferees and, hopefully, for
immunologists generally. These include the selection of subject areas or issues
that are timely and appropriate to the very considerable investment of effort,
time, funds, and the extensive involvement of committed colleagues; the
selection of conferees, focusing particularly on specialists and generalists who
have ideas, experience, points of view, and concepts to contribute; the dis-
tinctively loose-structured programs and their prevailing informality, with
assignments limited to the handful of discussion introducers; the use of expert
stenotypy to capture the dynamic flow of the discussions, providing partici-
pants with an opportunity to correct their remarks while they are still fresh
and vivid. This is crucial for the overall speed and effectiveness of the sub-
sequent editorial process. Last, but by no means least, is the great natural
beauty and tranquility of Brook Lodge — the conference site itself. As an
ideal environment favoring interactions and information exchange, it con-
tributes greatly to the quality and character of these immunology colloquia.
xv
INTRODUCTORY ΝΟΤΕ
The underlying philosophy of these conferences is that only under conditions
which truly facilitate interactions among experts and generalists in immu-
nology and allied fields does there develop cross-fertilization of ideas, con-
cepts, and assessment of the state of our information, with consequent pro-
jection of needs and opportunities. In the course of dissecting and evaluating
findings and points of view, and then integrating new ones, the interplay of
personalities is nothing short of remarkable. The sorting out process - for
each conferee offers his work or ideas to critical analysis - is extremely effec-
tive and represents peer judgment at its very best.
Effecting the transition from the stenotyped proceedings of these intensive
and lively discussions to the final publication involves application of special
criteria on behalf of the reader. The entire thrust of the editorial process has
been to adhere faithfully to the essential message and, insofar as possible, to
the style and personal quality of the individual contributors while increasing
the level of readability. In this manner it is sought to make the proceedings a
permanent record that is understandable and stimulating for a large and diverse
audience.
The products that have emerged have been original assessments and syntheses
of knowledge in major segments of immunology. It will be noted that although
the subjects discussed at these conferences ranged from tolerance to mediators
of cellular immunity and immune surveillance, what emerged has been a con-
tinuing, more probing assessment of our knowledge of the immune response
itself.
Maurice Landy
Chief, Allergy and Immunology Branch
Extramural Programs, National Institute of
Allergy and Infectious Diseases
xvi
I
ORGANIZATION AND MODULATION OF
CELL MEMBRANE RECEPTORS
Definition and scope of surveillance — Phenotypic diversity of struc-
tures of cells — Inter and intra species variations in surface antigens —
Surface structures peculiar to lymphoid cells — Coded arrangement
of membrane units confer cell surface individuality — Hypothesis of
the cell membrane grid — Application to tumor surveillance — Clarifi-
cation of the grid concept - Mechanisms by which changes in the
grid are effected — Antigenic modulation — Relationship between
histocompatibility and tumor antigens — Expression of HL-A antigens
on tumor cells — Density of grid units versus configuration — Turnover
of grid components.
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