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Progression from Acute to Chronic Disease in a Murine Parent-into-F₁ Model of Graft-Versus-Host Disease

Jolynne R. Tschetter^*, Edna Mozes and Gene M. Shearer^*,1

^* Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; and Department of Immunology, Weizmann Institute of Science, Rehovot, Israel

The parent-into-immunocompetent-F₁ model of graft-vs-host disease (GVHD) induces immune dysregulation, resulting in acute or chronic GVHD. The disease outcome is thought to be determined by the number of parental anti-F₁ CTL precursor cells present in the inoculum. Injection of C57BL/6 (B6) splenocytes into (B6 x DBA/2)F₁ (B6D2F₁) mice (acute model) leads to extensive parental cell engraftment and early death, whereas injection of DBA/2 cells (chronic model) results in little parental cell engraftment and a lupus-like disease. This study demonstrated that injection of BALB/c splenocytes into (BALB/c x B6)F₁ (CB6F₁) mice resulted in little engraftment of parental lymphocytes and the development of lupus as expected. Injection of B6 splenocytes into CB6F₁ initiated an initial burst of parental cell engraftment similar to that of B6 into B6D2F₁. However, the acute disease resolved, and the CB6F₁ mice went on to develop chronic GVHD with detectable Abs to ssDNA, dsDNA, and extractable nuclear Ags. Limiting dilution CTL assays determined that B6 splenocytes have CTL precursor frequencies of 1/1000 against both CB6F₁ and B6D2F₁, whereas DBA/2 and BALB/c splenocytes have a CTL precursor frequency of 1/20,000 for their respective F₁s. The Th cell precursor frequency for B6 anti-DBA/2 was 3-fold higher than that for B6 anti-BALB/c determined by limiting dilution proliferation assays. These results indicate the importance of adequate allospecific helper as well as effector T cells for the induction and maintenance of acute GVHD in this model, and presents an unexpected model in which initial acute GVHD is replaced by the chronic form of disease.

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