BONE-MARROW AND THYMUS EXPRESSION OF INTERFERON-GAMMA RESULTS IN SEVERE B-CELL LINEAGE REDUCTION, T-CELL LINEAGE ALTERATIONS, AND HEMATOPOIETIC PROGENITOR DEFICIENCIES

Interferon-gamma (IFN-gamma) is an immunoregulatory lymphokine that is primarily produced by T cells and natural killer cells. It has effect s on T-cell, B-cell, and macrophage differentiation and maturation. We have developed transgenic mice that express elevated levels of IFN-ga mma mRNA and protein by inserting multiple copies of murine IFN-gamma genomic DNA containing an Ig lambda-chain enhancer in the first intron . The founder line carrying eight copies of this transgene has eightfo ld to 15-fold more IFN-gamma-producing cells in the bone marrow and sp leen than do nontransgenic littermates. Transgenic mice show a pronoun ced reduction in B-lineage cells in the bone marrow, spleen, and lymph nodes. In addition, single positive (CD4(+),CD8(-) and CD4(-),CD8(+)) thymocyte numbers are increased twofold, yet the number of splenic T cells is reduced by 50%. There is also a twofold to threefold decrease in the frequency and total number of myeloid progenitors in the bone marrow. Granulomatous lesions and residual degenerating cartilaginous masses are also present in the bones of these mice. Overall, our data show that the abnormal expression of IFN-gamma in these transgenic mic e results in multiple alterations in the immune system. These animals provide an important model to examine the role of IFN-gamma expression on lymphoid and myeloid differentiation and function. This is a US go vernment work. There are no restrictions on its use.