Interleukin-12 prevents severe acute graft-versus-host disease (GVHD) and GVHD-associated immune dysfunction in a fully major histocompatibility complex haplotype-mismatched murine bone marrow transplantation model.
BACKGROUND
We have recently reported that interleukin (IL)-12 prevents acute graft-versus-host disease (GVHD)-induced mortality in a full major histocompatibility complex- plus multiple minor antigen-mismatched A/J-->B10 bone marrow transplantation (BMT) model. Because most patients have access to a haploidentical, one haplotype-mismatched donor, we have now investigated the protective effect of IL-12 against GVHD and GVHD-associated immune dysfunction in a haploidentical CBD2F1 (H2kxd) --> B6D2F1 (H2bxd) strain combination.


METHODS
GVHD was induced by injecting CBD2F1 marrow and spleen cells into lethally irradiated B6D2F1 mice.


RESULTS
In untreated control mice, GVHD resulted in 87% mortality by day 8 after BMT, with no survivors beyond day 17. Treatment with a single injection of IL-12 on the day of BMT led to 87% long-term survival, with no significant weight loss, diarrhea or GVHD skin changes. The majority of T cells recovering in these mice showed the CD62L+, CD44low, CD45RBhigh naive phenotype. These T cells showed specific tolerance to both host and donor histocompatibility antigens, but normal anti-third party (H2s) alloresponses in vitro. B-cell proliferative responses to lipopolysaccharide were also normal in IL-12-protected mice. Moreover, normal negative selection of thymocytes bearing T cell receptors with Vbeta that recognize endogenous superantigens was observed among CD4+CD8- thymocytes, indicating a lack of GVHD-associated thymic selection abnormalities in IL-12-protected allogeneic BMT recipients.


CONCLUSIONS
IL-12 provides permanent protection against an otherwise severe, rapidly lethal GVHD, with no clinical manifestations of chronic GVHD, immunosuppression or autoimmune features, in a full major histocompatibilty complex haplotype-mismatched murine BMT model.
Yang
Y G
YG
Transplantation Biology Research Center, Surgical Service, Massachusetts General Hospital/Harvard Medical School, Boston 02129, USA.
Dey
B
B
Sergio
J J
JJ
Sykes
M
M
D000208:Acute Disease; D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology*; D002417:Cattle; D002908:Chronic Disease; D006224:Cricetinae; D005260:Female; D006086:Graft vs Host Disease / Q000517:prevention & control*; D006239:Haplotypes / Q000276:immunology*; D018664:Interleukin-12 / Q000627:therapeutic use*; D008213:Lymphocyte Activation; D008285:Major Histocompatibility Complex / Q000276:immunology*; D051379:Mice; D008815:Mice, Inbred Strains; D051381:Rats; D012680:Sensitivity and Specificity; D013601:T-Lymphocytes / Q000276:immunology; D014019:Tissue Donors
D018664:Interleukin-12