Table 1

Caveats from animal models

  1. The conditioning regimen used to prepare the recipient: in murine GVHD studies, irradiation alone is typically used, although regimen intensity ranges from no conditioning in immune-competent or immune-deficient recipients to myeloablative doses of irradiation followed by marrow rescue. Irradiation often is used with large fraction doses and high dose rates not commonly used in patients. Typically, no chemotherapy is given along with irradiation, and chemotherapy-alone regimens are not commonly studied in acute GVHD models.

  2. The immunologic disparity between donor and recipient: a diverse array of mouse inbred strain combinations is used, resulting in a variety of MHC- and/or MiHA-disparate models. These different strain combinations have different Th1/Th2/Th17 as well as Treg content and can sway the dominance of CD4+ or CD8+ T-cell effectors in GVHD. Thus, conclusions in one model may not translate into other immunologically distinct models or into the clinic.

  3. The source of donor cells: typically, spleen cells and/or lymph node cells are added to the BM graft to provide a sufficient dose of T cells for the induction of GVHD in most murine strain combinations, in contrast to peripheral blood or bone marrow harvests used in human studies.

  4. The microbial baseline of the animal facility and the use of prophylactic antibiotics can alter the immunologic responses in GVHD and markedly affect the sensitivity and response to cytoreductive conditioning. Whereas in rodents, mice are housed under specific-pathogen free conditions since birth, humans are not. Therefore, extrapolation of murine data between laboratories may be difficult and clinical translation of such findings into HSCT recipients may be even more challenging, especially for those innate and adaptive immune responses most readily influenced by the microenvironment.

  5. Age of the donors and recipients: the majority of murine HSCT studies use primarily young adult mice and only on rare occasions older mice will be used. Older age in mice is known to alter APC capacity, thymopoiesis and peripheral T-cell recovery, and sensitivity to radiation.

 

  1. The conditioning regimen used to prepare the recipient: in murine GVHD studies, irradiation alone is typically used, although regimen intensity ranges from no conditioning in immune-competent or immune-deficient recipients to myeloablative doses of irradiation followed by marrow rescue. Irradiation often is used with large fraction doses and high dose rates not commonly used in patients. Typically, no chemotherapy is given along with irradiation, and chemotherapy-alone regimens are not commonly studied in acute GVHD models.

  2. The immunologic disparity between donor and recipient: a diverse array of mouse inbred strain combinations is used, resulting in a variety of MHC- and/or MiHA-disparate models. These different strain combinations have different Th1/Th2/Th17 as well as Treg content and can sway the dominance of CD4+ or CD8+ T-cell effectors in GVHD. Thus, conclusions in one model may not translate into other immunologically distinct models or into the clinic.

  3. The source of donor cells: typically, spleen cells and/or lymph node cells are added to the BM graft to provide a sufficient dose of T cells for the induction of GVHD in most murine strain combinations, in contrast to peripheral blood or bone marrow harvests used in human studies.

  4. The microbial baseline of the animal facility and the use of prophylactic antibiotics can alter the immunologic responses in GVHD and markedly affect the sensitivity and response to cytoreductive conditioning. Whereas in rodents, mice are housed under specific-pathogen free conditions since birth, humans are not. Therefore, extrapolation of murine data between laboratories may be difficult and clinical translation of such findings into HSCT recipients may be even more challenging, especially for those innate and adaptive immune responses most readily influenced by the microenvironment.

  5. Age of the donors and recipients: the majority of murine HSCT studies use primarily young adult mice and only on rare occasions older mice will be used. Older age in mice is known to alter APC capacity, thymopoiesis and peripheral T-cell recovery, and sensitivity to radiation.

 

GVHD indicates graft-versus-host disease; MHC, major histocompatibility complex; MiHA, minor histocompatibility antigen; Treg, regulatory T cell; BM, bone marrow; HSCT, hematopoietic stem cell transplantation; and APC, antigen-presenting cell.

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