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

Abstract

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.

An Official American Thoracic Society Research Statement: Noninfectious Lung Injury after Hematopoietic Stem Cell Transplantation: Idiopathic Pneumonia Syndrome

“…Several murine models of lung injury after HSCT have been established using a variety of strain combinations and conditioning regimens (Table 4). They include a lethally irradiated major histocompatibility complex (MHC)-matched, multiple minor antigen mismatch (6,20,68,172); a complete MHC mismatch model with and without cyclophosphamide (7, 69), lethally irradiated, haploidentical, parent into F1 model (20,146,147,165); a MHC class I mismatch (68,70); a MHC class II mismatch (68); and a syngeneic HSCT model using high-dose chemotherapy (71).…”

Intervention of MAdCAM-1 or fractalkine alleviates graft-versus-host reaction associated intestinal injury while preserving graft-versus-tumor effects

“…In the early phase of allo-BMT, circulating naïve donor T cells rapidly enter into the host secondary lymphoid tissues through adhesion molecule L-selectin, ␣4 integrin, ␣4␤7, MAdCAM-1, and chemokine receptor CCR5, and preventive intervention of these molecules inhibit the development of anti-host CTL and ameliorate GVHD [14 -16]. In the late phase, it has been reported that anti-host CTL infiltrate into liver via LFA-1-ICAM-1 interaction and CCR5-MIP-1␣ interaction and into the intestine via CXCR3-CXCR3 ligand interaction [17][18][19][20]. However, molecular interactions essential for the development of tissue-specific GVHD are not fully established, because severity of GVHD induced by CCR5 Ϫ/Ϫ donor cells depends on the conditioning regimen [21], and GVHD to MHC is not reduced in recipients of CXCR3 Ϫ/Ϫ donor cells [20].…”

The influence of macrophage inflammatory protein‐1α on protective immunity mediated by antiviral cytotoxic T cells

“…14,15 The implication that MIP-1a increases the risk of immune-mediated damage to the host is supported by the observations that MIP-1a de®ciency can protect against the development of experimental autoimmune encephalitis (EAE) 16 type II collagen-induced arthritis and graft versus host disease (GVHD) in mice. 17,18 The relative in¯uence of MIP-1a on antigen-speci®c versus non-speci®c immune responses was not addressed in the studies described above.…”