The Journal of Experimental Medicine, Vol 132, 181-197,
Copyright © 1970 by The Rockefeller University Press
AN ANALYSIS OF GRAFT-VERSUS-HOST DISEASE IN SYRIAN HAMSTERS
:
II. THE EPIDERMOLYTIC SYNDROME: STUDIES ON ITS PATHOGENESIS
J. Wayne Streilein M.D.1 and
R. E. Billingham F.R.S.1
1 From the Departments of Medical Genetics and Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104
The epidermolytic syndrome that can be obtained at will in F1 hybrid hamsters by the cutaneous inoculation of adequate doses of parental strain lymphoid cells has been investigated to determine whether the cutaneous lesions are due to an autoimmune process arising from the severe, initial GVH reactions in the skin. It was amply demonstrated that inoculation of donor cells into the skin was of crucial importance to the development of epidermolysis. Parental strain lymphoid cells in similar doses delivered by any other route into normal F1 hybrids failed absolutely to incite the acute syndrome. If "immune lymphocyte transfer" reactions incited by donor cells in the host's skin were surgically removed at timed intervals after inoculation, only complete excision within 24 hr prevented the appearance of epidermolysis in F1 hybrid hosts, indicating that inoculated donor cells must remain within the confines of the skin for approximately 24 hr in order to evoke the disease, persistence for longer periods of time being unnecessary for the subsequent course of the disease. However, reconstitution experiments involving the intramuscular inoculation of suspensions containing mixtures of donor cells and host lymphoid cells, in the presence or absence of epidermal cells, unequivocally indicated that no intimate exposure of lymphoid cells to putative skin-specific antigens was essential. Similarly, the elicitation of generalized epidermolysis in F1 hybrids irradiated with 300 r and then inoculated intravenously with donor cells casts further doubt on the pathogenic importance of the skin as a source of tissue-specific antigen.
The results of subsequent experiments indicated that host leukocytes, rather than parenchymal cells of the dermis or the epidermis, were important contributors of the transplantation antigenic stimulus. Moreover, a series of experiments, using (CB x MHA)F1 hybrid hosts that had been lethally irradiated and reconstituted with bone marrow cells from ALS-treated MHA donors, indicated that from 6 to 10 wk after reconstitution—when direct and immune lymphocyte transfer reactions showed a virtual absence of native F1 leukocytes from the circulation—donor cells obtained from specifically sensitized MHA donors were completely ineffective in inducing epidermolysis, while equivalent lymphoid cell inocula derived from CB donors evoked the cutaneous disease irrespective of the time elapsed since reconstitution.
To explain these findings it is postulated that in hamsters, the primary targets in graft-versus-host disease incited by the intracutaneous inoculation of donor cells are leukocytes originating in bone marrow or lymph node, or both.
Submitted on February 12, 1970
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