A new xenograft model for graft-versus-host disease by intravenous transfer of human peripheral blood mononuclear cells in RAG2-/- gammac-/- double-mutant mice.
The safe application of new strategies for the treatment of graft-versus-host disease (GVHD) is hampered by the lack of a clinically relevant model for preclinical testing. Current models are based on intraperitoneal transfer of human peripheral blood mononuclear cells (huPBMCs) into NOD-SCID (nonobese diabetic-severe combined immunodeficient)/SCID mice. Intravenous transfer would be preferred but this has always been ineffective. We developed a new model for xenogeneic GVHD (X-GVHD) by intravenous transfer of huPBMCs into RAG2-/- gammac-/-mice. Our results show a high human T-cell chimerism of more than 20% (up to 98%) in more than 90% of mice, associated with a consistent development of XGVHD within 14 to 28 days and a total mortality rate of 85% shorter than 2 months. After murine macrophage depletion, engraftment was earlier and equally high with lower doses of huPBMCs. Human macrophages were also absent in these mice. Purified huCD3+ cells showed a similar X-GVH effect with contribution of both CD4 and CD8 phenotypes. Human immunoglobulins and cytokines were produced in diseased mice. One of 30 mice developed chronic X-GVHD with skin histology similar to human GVHD. In conclusion, we present a new model for X-GVHD by intravenous transfer of huPBMCs in RAG2-/- gammac-/- mice. Murine and human macrophages do not seem to be necessary for acute X-GVHD in this model.
van Rijn
Rozemarijn S
RS
Jordan Laboratory for Hemato-Oncology, Department of Hematology, University Medical Center Utrecht, The Netherlands.
Simonetti
Elles R
ER
Hagenbeek
Anton
A
Hogenes
Marieke C H
MC
de Weger
Roel A
RA
Canninga-van Dijk
Marijke R
MR
Weijer
Kees
K
Spits
Hergen
H
Storm
Gert
G
van Bloois
Louis
L
Rijkers
Ger
G
Martens
Anton C M
AC
Ebeling
Saskia B
SB
D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D016516:CD4-CD8 Ratio; D004002:Clodronic Acid / Q000494:pharmacology; D016207:Cytokines / Q000097:blood; D004268:DNA-Binding Proteins / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D015329:Gene Rearrangement, T-Lymphocyte / Q000235:genetics; D006086:Graft vs Host Disease / Q000276:immunology* / Q000503:physiopathology; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D007075:Immunoglobulin M / Q000097:blood; D007275:Injections, Intravenous; D007668:Kidney / Q000166:cytology; D007963:Leukocytes, Mononuclear / Q000637:transplantation*; D008099:Liver / Q000166:cytology; D008168:Lung / Q000166:cytology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009687:Nuclear Proteins; D010641:Phenotype; D012867:Skin / Q000166:cytology; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000502:physiology; D017186:Titrimetry; D018183:Transplantation Chimera; D014183:Transplantation, Heterologous; D019737:Transplants
D000963:Antimetabolites; D016207:Cytokines; D004268:DNA-Binding Proteins; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D009687:Nuclear Proteins; C499311:RAG2 protein, human; C499308:Rag2 protein, mouse; C064655:V(D)J recombination activating protein 2; D004002:Clodronic Acid