THE ROCKEFELLER INSTITUTE FOR MEDICAL RESEARCH

66TH STREET AND YORK AVENUE
NEW YORK @2I,N_Y.

16 December 1959

Dr. Joshua Lederberg
Professor of Genetics
Stanford University

Stanford, California

Dear Joshua:
Your letter was most interesting and | belatedly reply.

It is true that in my mind's eye | saw this originally as a disease of generaiized
hyper-responsiveness. This was so despite absence of specific evidence of antibody form-
ation to foreign, non-human antigens. However, now | think the true story may be some-
what different. E.g., we have immunized a group of patients who were in remission and
off steroids to typhoid and compared their response to supposedly normal controis. Despite
three booster shots, these persons did not develop titers in excess of the controis. We are
now beginning a study of T agglutinin titers in iupus patients. At this time it must be
said that there is no solid evidence of an excessive response to antigens other than those
from human tissues. If future studies confirm this, then the hyper-responsiveness of the
patients will be jimited to their own tissues (and perhaps other human tissues as in the
blood group reactions). Such a situation might represent an interesting application of
clonal selection with the ever-present autologous tissues acting as the antigens which
stimulate growth of the clones.

It would indeed be interesting to titer sera against rare Salmonelia antigens and
perhaps we should do that as a part of this study.

Your thoughts about the relationship between SLE and agammaglobulinemia are
quite interesting. We are in the process of attempting to conduct tissue cuiture and trans-
plantation experiments, using tissues and cells of these patients. | anticipate a great deal
of difficulty, but if we can succeed in crossing the species barrier for any period of time,
we may be able to examine more closely the growth characteristics, protein synthesis, and
cyto-toxic effects of some of these presumably abnormal lymphoid celis. Perhaps | am
wrong, but research in this field seems stymied by the lack of an experimental mode: .
Transplantation may give us some leads.
One interesting facet that seéms fairly well established is the existence of
bizarre rheumatoid=like serologic abnormalities in ciinically normal relatives of
patients with SLE. This, coupled with the high incidence of rheumatoid arthritis in
other relatives, suggests that there is some sort of familial immunoiogic abnormality
which may express itself as either disease or only as a pecuiiar immunologic responsive-
ness devoid of symptoms. In such families we may also find fertile tissue for study.

| look forward to your results with the fluorescence experiments.
Under separate cover | will send the reprints you requested.
With best regards.

Sincerely yours,

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Haisted \ Holman, M.D.