Pneumopathies of the graft-versus-host reaction. Alveolitis associated with an increased level of tumor necrosis factor mRNA and chronic interstitial pneumonitis.

Irradiated (CBA x B10)F1 hybrid mice were injected with parental T lymphocyte-depleted bone marrow cells, (BMC), or with parental BMC together with T lymphocytes in an amount inducing greater than 80% mortality by day 40. Recipients of T cell depleted BMC did not show any mortality or significant pulmonary alterations, whereas recipients of BMC with T lymphocytes showed an alveolitis during the acute phase of the graft-versus-host reaction (GVHR) (day 15 to 25), characterized by: (a) alveolar hemorrhages, (b) increase of the number of alveolar leukocytes, (c) platelet microthrombi, (d) damage of the alveolar endothelial and epithelial cells, (e) increase of the turnover rate of the alveolar cells as shown by 3HTdR labelling, (f) increase in cell number and protein content of the bronchoalveolar lavage. These lesions were severe in the B10 versus F1, but absent in the reciprocal CBA versus F1 GVHR combination. The alveolitis was associated with a marked increase in the level of tumor necrosis factor-alpha mRNA, as shown by Northern gel analysis of lung RNA and was partially prevented by passive immunization with a rabbit anti-mouse tumor necrosis factor-alpha antibody. Mice examined after 25 days of evolution (i.e., chronic GVHR) presented an interstitial pneumonitis characterized by the accumulation of mononucleated cells, resembling large granular lymphocytes, which infiltrated first the intima of the blood vessels, and subsequently the interstice and the bronchi. These data demonstrate that the GVHR alone (in the absence of chemotherapy or overt infection) can induce two types of pneumopathies, an alveolitis and an interstitial pneumonitis.