Involution of thymus and lymphoid depletion in mice expressing the hTNF transgene.

Tumour necrosis factor (TNF) is involved in the pathogenesis of several diseases. In mice, human TNF signals only through p55, one of two murine TNF receptors. We here report a study of growth, viability and morphological alterations in transgenic mice expressing a low constitutive and tissue-restricted level of human TNF in vivo. The transgene was expressed solely in T cells. The transgenic mice showed a marked failure to thrive and a rapid cellular depletion in spleen and thymus. Slight fibrosis was seen in most tissues investigated, in addition to immature adipose tissue and irregular lymphocytic areas. Serum levels of hTNF were only slightly increased in the transgenic mice, enough, however, to cause an inflammatory reaction. All the symptoms were abrogated by an inhibitory hTNF antibody, demonstrating the essential role of hTNF in this phenotype. Transgenic mice constitute a multidimensional system allowing observation of disease processes over time in all tissues. The effects of hTNF were seen first and foremost in the lymphoid organs of the transgenic mice, verifying their cells as major targets at low levels of hTNF expression in the T-cell compartments. Chronic, low levels of TNF expression cause profound disturbances in lymphoid tissue development resulting in cachexia and premature death.