Donor-derived IL-15 is critical for acute allogeneic graft-versus-host disease

Abstract

Interleukin-15 (IL-15) is a pleiotropic proinflammatory cytokine with inefficient posttranscriptional processing. We hypothesized that endogenous IL-15 could affect disease progression in the well-described C57Bl/6 (B6) 3 (C57Bl/6 ؋ DBA/2) F1 hybrid ( IntroductionBone marrow transplantation (BMT) is a potentially curative therapy for patients with heritable immunodeficiencies and malignant diseases including leukemia, lymphoma, and myeloma. 1 While the conditioning regimen for BMT leads to direct tumor destruction, donor-derived allogeneic T cells can exert an important graft-versus-tumor (GVT) effect: recipients of allogeneic transplants have a decreased probability of relapse compared with recipients of autologous, syngeneic, or T-cell-depleted bone marrow transplants. 2,3 However, allogeneic BMT also carries a significant risk for graft-versus-host disease (GVHD), an immunologic attack of allogeneic donor T lymphocytes against normal recipient tissues, the magnitude of which depends in large part on the degree of HLA incompatibility between donor and recipient. Even with appropriate prophylaxis, the incidence of acute GVHD ranges from 30% in HLA-identical donor-recipient pairs to 70% for donorrecipient pairs HLA-incompatible at 2 loci. 1,4 Thus, GVHD remains the most significant obstacle to the wider application of BMT for the treatment of malignancy.GVHD is characterized by a cycle of tissue destruction and inflammation initiated by the preparative regimen for transplantation and propagated by alloreactive donor T cells. 5 Transplant recipients are prepared for BMT with a regimen that obliterates their current bone marrow stores and potentially their residual leukemia. However, this regimen is also highly toxic to the gastrointestinal system and allows release of gram-negative bacterial lipopolysaccharide (LPS) across the intestinal mucosa. 6 LPS is a potent stimulator for the production of tumor necrosis factor ␣ (TNF-␣), interleukin-1 (IL-1), and IL-12. 6,7 IL-12 polarizes donorderived T cells toward a proinflammatory Th1/Tc1 phenotype, producing interferon ␥ (IFN-␥) and TNF-␣; 8,9 IFN-␥ and TNF-␣ induce major histocompatibility complex (MHC) expression by host-derived antigen-presenting cells (APCs), which results in efficient presentation of alloantigen to donor-derived T cells. 10,11 These donor-derived Th1/Tc1-polarized T cells in turn produce IL-2, expand, and infiltrate host epithelial tissues. Thus, the inflammation of acute GVHD is influenced in large part by the cytokine cascade within the host after transplantation.The role of IL-15, a T-and natural killer (NK) cell growth factor, in allogeneic GVHD has not been addressed. Originally isolated because of its ability to restore T-cell growth in the presence of IL-2-neutralizing antibodies, 12,13 IL-15 mRNA is widely and abundantly expressed in multiple tissues. However, IL-15 is inefficiently translated and secreted with multiple posttranscriptional checkpoints. [14][15][16] 36,37 We therefore hypothesized that alteration of endogenous IL-15 produ...

OX40 (CD134) engagement drives differentiationof CD4+ T cells to effector cells

“…Two other cytokine receptors acting through the common gamma chain, IL-15Ra and IL-7R, were also induced (Table 2). Like IL-2R, the IL-15 and IL-7 receptors have been implicated in survival and differentiation of T cells [35][36][37]. Notably, anti-OX40 also induced mRNA for IL-12Rb2 (Table 2), consistent with the strong response to stimulation with IL-12 and IL-18 in the anti-OX40-treated T cells.…”

Interleukin-15 administration increases graft-versus-tumor activity in recipients of haploidentical hematopoietic SCT

“…On the other hand, IL-15 administration by increasing post-transplant T-cell reconstitution might stimulate GVHD development in T-cell replete models. 3,23 We have demonstrated that post-transplant IL-15 administration enables a very low-dose T-cell infusion to generate antitumor activity, mitigating the risk of GVHD. We have also found that timing is a critical factor for changing the balance of GVL/GVH to GVL direction.…”

Expression of interleukin 15 in primary adult acute lymphoblastic leukemia

“…3,[7][8][9][10] Concerning the clinical relevance of IL-15 in hematopoietic malignancies, elevated IL-15 levels have been shown to affect the initial response to therapy and were associated with malignant transformation, including organ infiltration and disease progression, such as relapse. 3,[10][11][12][13] In adult ALL, clinical studies have defined immunophenotype and molecular genetic markers, as well as the duration of first remission, as the most significant independent prognostic determinants. 1,2,14 However, the improved understanding of the biology of adult ALL and identification of specific risk factors remains an important issue.…”