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SERVICES
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¢ Wa DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service
cp. National Institutes of Health

National Heart, Lung, and
Blood Institute
Bethesda, Maryland 20892

March 26, 1987

    

* Dr. Joshua Lederberg
President
Rockefeller University
1230 York Avenue
New York, NY 10021

MAR 39 1987

Q 6
LOE oF THe pre

Dear Josh:

David Hamburg had written me relating to the husband of one of his for-
mer students (I believe he has sent you a copy of his letter to me). I
thought you might be interested in the follow-up. I am also enclosing,
for your interest, the articles I sent to Dr. Benedict as well as a copy
of an article specifically related to therapy which is scheduled for
publication in the New England Journal of Medicine next month.

I was interested in your thoughts about approaches to AIDS. There are
two areas that we have been considering in relation to this disorder.

First, as you know, although originally it was thought that the CD4+
(helper/inducer) T-lymphocyte was the only target cell of the virus, it
is now recognized that mononuclear phagocytes (including human alveolar
macrophages) can be infected with the virus (perhaps because the
alveolar macrophage also expresses the CD4 antigen). In this context,
since the alveolar macrophage plays a major role in defending the lung
(and one of the major problem these individuals eventually die from is
lung infection, particularly with opportunistic organisms), HTLV-III
infection of normal human alveolar macrophages would be an interesting
model in regards the effect of integration of the virus into the
alveolar macrophage genome and its effect on other macrophages genes
(i.e., is the insertion random, are certain classes of genes more selec-
tively affected, etc.).

Second, we have been interested in the concept of very restricted sub-
sets of T-lymphocytes as being targets (as well as effectors) in disor-
ders of the lower respiratory tract. For example, in sarcoidosis, we
have evidence that there is a limited clonal population of T-lymphocytes
that may be involved in the disorder (see attached paper submitted for
publication). In AIDS, despite the fact that the CD4+ lymphocytes in the
blood are decreased in number, there is an expansion in the numbers of
lymphocytes in the lung, particularly CD8+ (suppressor/cytotoxic)
T-lymphocytes. This is of interest because (although not described in
the paper I have enclosed) we have some recent evidence that in sar-
coidosis at least some of the "clonal" T-cells found in the lung are

 
 
Dr. Joshua Lederberg - Page 2

CD8+, despite the fact that the disease is one in which there is an
accumulation of CD4+ T-cells at the site of disease. This has let us to
wonder whether or not there may be very limited subsets of CD8+ T-cells
that are involved in inflammatory reactions in organs (such as the lung)
generally i.e., very restricted T-cell subsets that "direct" these
chronic inflammatory reactions. With our ability to recover compartmen-
talized populations of T-cells from the lower respiratory tract and com-
pare those with the blood, it may be possible to clone (using single
cell cloning techniques) the important representatives of these regula-
tory T-cells subsets. As an alternative approach, we have already made a
genomic DNA library from the T-cells of the lower respiratory tract of a
patient with very active sarcoidosis. This is being used to attempt to
"pull-out" the rearranged genome of the T-cell antigen receptor $-chain
involved in such regulatory T-cell subsets.

I am looking forward to discussing this in more detail with you when we
meet again.

Sincerely yours,

pe

Ronald G. Crystal, M.D.
Chief, Pulmonary Branch
National Heart, Lung, and Blood Institute

Enclosures (3)

RGC: las