Graft‐versus‐Host Disease in Dog and Man: The Seattle Experience

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Abstract
In dog and in man a marrow graft from a donor genetically identical for the major histocompatibility complex is followed by significant graft-versus-host disease (GvHD) in approximately one-half of the recipients, despite the administration of post-grafting immunosuppressive therapy. Controlled trials comparing post-grafting therapy using methotrexate or cyclosporine have shown no difference in long-term survival, although cyclosporine reduces the incidence of mucositis and is associated with somewhat earlier engraftment. Observations in the canine model indicating efficacy of a combination of a brief course of methotrexate with the cyclosporine regimen are now being tested in patients, with early results indicating a reduction in GvHD and an improved survival. In both species, failure to administer immunosuppression after grafting is associated with a high incidence of acute GvHD and an adverse effect on survival. Removal of donor T cells from the marrow inoculum may reduce the incidence of acute GvHD but at the price of a higher likelihood of subsequent graft failure. Studies of canine and human chimeras are in agreement with murine data indicating a principal role for T cells in the pathogenic mechanism of GvHD. Chimera lymphocytes (of donor origin) from dogs and patients with acute GvHD proliferate in response to previously stored host cells, and lymphocytes cytotoxic to host target cells are seen in patients with GvHD. Our observations indicate a direct, rather than an indirect, role for T cells since lymphocytes from donors sensitized to chimeric skin grafts can cause lethal GvHD when infused into stable chimeric recipients. "Specific" suppressor cells may play a role in maintaining stable graft-host tolerance while "nonspecific" suppressor cells may be responsible for the impaired immune defenses in patients with chronic GvHD. Chronic GvHD, which resembles systemic collagen vascular disease, occurs in approximately 40% of matched recipients, particularly following acute GvHD, and is more frequent in older patients. Efforts to treat both acute and chronic GvHD with steroids, antithymocyte globulin, cyclosporine and azathioprine are only partially and unpredictably effective. Data in dogs pointed out the feasibility of transplants from partially matched related donors or matched unrelated donors, an approach that is now being actively pursued in human patients. Marrow transplants from HLA-partially matched family members resulted in a higher incidence of acute GvHD.(ABSTRACT TRUNCATED AT 400 WORDS)