The Parent-into-F1 Murine Model in the Study of Lupus-Like Autoimmunity and CD8 Cytotoxic T Lymphocyte Function

Abstract

The transfer of homozygous C57Bl/6 (B6) or DBA/2 (DBA) parental strain T cells into normal B6D2F1 mice in the parent-into-F1 (p → F1) model results in a graft-vs.-host disease (GVHD) that takes one of the following two forms: (a) acute GVHD seen with B6 → F1 mice and mediated by donor CD8 cytotoxic T cells that eliminate host lymphocytes and (b) a chronic lupus-like GVHD seen with DBA → F1 mice and mediated by donor CD4 T cell cognate help to autoreactive B cells resulting in autoantibody production and renal disease similar to human lupus. Importantly, these two phenotypes can be distinguished by flow cytometry as early as 2 weeks after donor cell transfer. The p → F1 model can be used to screen for agents that alter lupus development. Additionally, the model is useful for preclinical screening of biologic agents with immunomodulatory potential. Agents that selectively inhibit CD8 T cell function will convert acute GVHD to chronic GVHD in B6 → F1 mice. Conversely, agents that promote CD8 CTL function will convert chronic GVHD to acute GVHD in DBA → F1 mice. Agents that completely suppress T cell function will block both phenotypes. The model is also useful for examining the effects of T cell mutations by transferring mutant T cells into wild-type hosts and assessing the effects on disease phenotype. Differences observed from wild-type T cells → F1 can be directly ascribed to alterations in mutant T cell function. Because of the early 2-week phenotype development, the p → F1 model is well suited to screening of potential immunomodulatory therapeutic compounds and the assessment of T cell mutations on in vivo function.

TGF-β–Induced CD4+Foxp3+ T Cells Attenuate Acute Graft-versus-Host Disease by Suppressing Expansion and Killing of Effector CD8+ Cells

“…Donor and host cells can be distinguished by staining H2-K d and H2-K b since donor cells are H2-K b+/d− and host cells are H2-K b+/d+ . Near 50% donor cells can be observed in this aGVHD model 2 weeks after cell transfer that is consistent with a parent (B6)-to-F1 aGVHD model others have previously reported (19) (Fig. 1A).…”

The Biology of Chronic Graft-versus-Host Disease: A Task Force Report from the National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease

“…Historically, the most frequently utilized chronic GVHD strain combination is a parent into semi-allogeneic F1 model that result in lupus-like manifestations (300) (Table 4). Following the infusion of unfractionated, parental, splenocytes, GVHD is initiated by donor CD4+ T-cell activation in response to host allogeneic MHC class II antigens, resulting in cognate donor CD4+ T-cell help to host B cells.…”

“…Acknowledged weaknesses of this model include the lack of clinical correlates of human chronic GVHD, incomplete donor engraftment, and the absence of radiation- or conditioning-regimen tissue injury. Nonetheless, novel potential targets for chronic GVHD intervention have been illustrated through this model, including CD137 agonist therapy and anti-TNF p55 subunit blockade (300, 301). …”

CTL-Promoting Effects of IL-21 Counteract Murine Lupus in the Parent→F1 Graft-versus-Host Disease Model

“…In the C57BL/6 (B6)→F1 aGVHD model, the transfer of normal parental CD4 and CD8 T cells into unirradiated normal F1 mice results in donor CD4 T cell activation and initial help for host B cells that is counteracted by the generation of donor CD8 CTLs that eliminate host splenic lymphocytes and particularly B cells, resulting in a lymphopenic state (32). In the DBA/2J (DBA)→F1 cGVHD model, the transfer of DBA splenocytes into F1 mice results in a lupuslike cGVHD as a result of the combination of donor CD4 T cell allorecognition and help for host B cells and impaired donor CD8 CTL effectors (30).…”