Macrophage inflammatory protein-2 (MIP-2)/CXCR2 blockade attenuates acute graft-versus-host disease while preserving graft-versus-leukemia activity

2012 ◽  
Vol 426 (4) ◽  
pp. 558-564 ◽  
Author(s):  
Kyung-Ah Cho ◽  
So-Youn Woo ◽  
Yoon Shin Park ◽  
Min Hwa Park ◽  
Kyung-Ha Ryu
Keyword(s):  
Graft Versus Host Disease ◽  
Host Disease ◽  
Graft Versus Host ◽  
Graft Versus Leukemia ◽  
Inflammatory Protein ◽  
Macrophage Inflammatory Protein ◽  
Acute Graft

T-lymphocyte production of macrophage inflammatory protein-1α is critical to the recruitment of CD8+ T cells to the liver, lung, and spleen during graft-versus-host disease

Blood ◽  
2000 ◽  
Vol 96 (9) ◽  
pp. 2973-2980 ◽  
Author(s):  
Jonathan S. Serody ◽  
Susan E. Burkett ◽  
Angela Panoskaltsis-Mortari ◽  
Judith Ng-Cashin ◽  
Eileen McMahon ◽  
...  
Keyword(s):  
T Cells ◽  
Graft Versus Host Disease ◽  
Cd8 T Cells ◽  
Class I ◽  
Wild Type ◽  
Host Disease ◽  
Graft Versus Host ◽  
Inflammatory Protein ◽  
Donor T Cells ◽  
Macrophage Inflammatory Protein

To investigate the mechanism by which macrophage inflammatory protein-1α (MIP-1α) affects graft-versus-host disease (GVHD), the expression and function of MIP-1α in 2 murine models of GVHD were evaluated. In irradiated class I and class II disparate recipients, the expression of messenger RNA (mRNA) and protein for MIP-1α was significantly increased in GVHD target organs after transfer of allogeneic lymphocytes compared to syngeneic lymphocytes. When lymphocytes unable to make MIP-1α were transferred, there was a decrease in the production of MIP-1α in the liver, lung, and spleen of bm1 (B6.C-H2bm1/By) and bm12 (B6.C-H2bm12/KhEg) recipients compared to the transfer of wild-type splenocytes. At day 6 there was a 4-fold decrease in the number of transferred CD8+ T cells in the lung and approximately a 2-fold decrease in the number of CD8+ T cells in the liver and spleen in bm1 recipients after transfer of MIP-1α–deficient (MIP-1α−/−) splenocytes compared to wild-type (MIP-1α+/+) splenocytes. These differences persisted for 13 days after splenocyte transfer. In contrast, the number of donor CD4+ T cells found in the liver and lung was significantly increased after the transfer of MIP-1α−/− compared to wild-type splenocytes in bm12 recipients from day 6 through day 10. Thus, the transfer of allogeneic T cells was associated with the enhanced expression of MIP-1α in both a class I and class II mismatch setting. However, the increased expression only led to enhanced recruitment of CD8+, but not CD4+, donor T cells. Production of MIP-1α by donor T cells is important in the occurrence of GVHD and functions in a tissue-dependent fashion.

Pretreatment of donors with interleukin-18 attenuates acute graft-versus-host disease via STAT6 and preserves graft-versus-leukemia effects

Blood ◽  
2003 ◽  
Vol 101 (7) ◽  
pp. 2877-2885 ◽  
Author(s):  
Pavan Reddy ◽  
Takanori Teshima ◽  
Gerhard Hildebrandt ◽  
Debra L. Williams ◽  
Chen Liu ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Allogeneic Bone ◽  
Interleukin 18 ◽  
Host Disease ◽  
Graft Versus Host ◽  
Allogeneic Bmt ◽  
Graft Versus Leukemia ◽  
Ifn Γ ◽  
Acute Graft

Interleukin-18 (IL-18) is a unique cytokine that modulates both TH1/TH2 responses, but its ability to modulate diseases through induction of TH2 cytokines is unclear. It has been shown to play an important role in allogeneic bone marrow transplantation (BMT). Because immune responses of allogeneic BM donors may affect acute graft-versus-host disease (GVHD), we investigated the effect of pretreating BM transplant donors with IL-18 on the severity of acute GVHD using a well-characterized experimental BMT model (BALB/c→B6). Pretreatment of allogeneic BM transplant donors with IL-18 significantly improved survival (80% vs 0%; P < .001), and reduced clinical, biochemical, and pathologic indices of acute GVHD in BM transplant recipients. IL-18 pretreatment was associated with reduced interferon γ (IFN-γ) and greater IL-4 secretion by donor T cells after BMT. Acute GVHD mortality was reduced when IL-18 was administered to donors deficient in IFN-γ and signal transducer and activator of transcription 4 (STAT4) but not STAT6 signaling molecules, suggesting a critical role for STAT6 signaling in IL-18's protective effect. IL-18 treatment did not alter donor CD8+ cytotoxic T-lymphocyte (CTL) activity and preserved graft-versus-leukemia (GVL) effects after allogeneic BMT (70% vs 10%; P < .01). Together these data illustrate that pretreatment of donors with IL-18 prior to allogeneic BMT attenuates acute GVHD in a STAT6-dependent mechanism while preserving GVL effects.

Sign in / Sign up

Export Citation Format

Share Document