Human peripheral blood leucocyte non-obese diabetic-severe combined immunodeficiency interleukin-2 receptor gamma chain gene mouse model of xenogeneic graft-versus-host-like disease and the role of host major histocompatibility complex.
Immunodeficient non-obese diabetic (NOD)-severe combined immune-deficient (scid) mice bearing a targeted mutation in the gene encoding the interleukin (IL)-2 receptor gamma chain gene (IL2rgamma(null)) engraft readily with human peripheral blood mononuclear cells (PBMC). Here, we report a robust model of xenogeneic graft-versus-host-like disease (GVHD) based on intravenous injection of human PBMC into 2 Gy conditioned NOD-scid IL2rgamma(null) mice. These mice develop xenogeneic GVHD consistently (100%) following injection of as few as 5 x 10(6) PBMC, regardless of the PBMC donor used. As in human disease, the development of xenogeneic GVHD is highly dependent on expression of host major histocompatibility complex class I and class II molecules and is associated with severely depressed haematopoiesis. Interrupting the tumour necrosis factor-alpha signalling cascade with etanercept, a therapeutic drug in clinical trials for the treatment of human GVHD, delays the onset and progression of disease. This model now provides the opportunity to investigate in vivo mechanisms of xenogeneic GVHD as well as to assess the efficacy of therapeutic agents rapidly.
King
M A
MA
Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
Covassin
L
L
Brehm
M A
MA
Racki
W
W
Pearson
T
T
Leif
J
J
Laning
J
J
Fodor
W
W
Foreman
O
O
Burzenski
L
L
Chase
T H
TH
Gott
B
B
Rossini
A A
AA
Bortell
R
R
Shultz
L D
LD
Greiner
D L
DL
D000818:Animals; D000068800:Etanercept; D005260:Female; D006086:Graft vs Host Disease / Q000188:drug therapy / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000627:therapeutic use; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007275:Injections, Intravenous; D053631:Interleukin Receptor Common gamma Subunit / Q000235:genetics*; D017493:Leukocyte Common Antigens / Q000032:analysis; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000637:transplantation*; D007959:Lymphocyte Culture Test, Mixed; D008285:Major Histocompatibility Complex; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D023421:Models, Animal; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use; D014018:Tissue Distribution; D014183:Transplantation, Heterologous; D014916:Whole-Body Irradiation
D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D053631:Interleukin Receptor Common gamma Subunit; D018124:Receptors, Tumor Necrosis Factor; D017493:Leukocyte Common Antigens; D000068800:Etanercept