Abstract
Allogeneic hematopoietic cell transplantation (allo-HCT) is performed with curative intent for high- risk blood cancers and bone marrow failure syndromes; yet the development of acute and chronic graft-vs.-host disease (GVHD) remain preeminent causes of death and morbidity. The IL-12 family of cytokines is comprised of IL-12, IL-23, IL-27, IL-35, and IL-39. This family of cytokines is biologically distinct in that they are composed of functional heterodimers, which bind to cognate heterodimeric receptor chains expressed on T cells. Of these, IL-12 and IL-23 share a common β cytokine subunit, p40, as well as a receptor chain: IL-12Rβ1. IL-12 and IL-23 have been documented as proinflammatory mediators of GVHD, responsible for T helper 1 (Th1) differentiation and T helper 17 (Th17) stabilization, respectively. The role of IL-27 is less defined, seemingly immune suppressive via IL-10 secretion by Type 1 regulatory (Tr1) cells yet promoting inflammation through impairing CD4+ T regulatory (Treg) development and/or enhancing Th1 differentiation. More recently, IL-35 was described as a potent anti-inflammatory agent produced by regulatory B and T cells. The role of the newest member, IL-39, has been implicated in proinflammatory B cell responses but has not been explored in the context of allo-HCT. This review is directed at discussing the current literature relevant to each IL-12-family cytokine and cognate receptor engagement, as well as the consequential downstream signaling implications, during GVHD pathogenesis. Additionally, we will provide an overview of translational strategies targeting the IL-12 family cytokines, their receptors, and subsequent signal transduction to control GVHD.
Highlights
Specialty section: This article was submitted to Alloimmunity and Transplantation, a section of the journal Frontiers in Immunology
IL-12 and IL-23 have been documented as proinflammatory mediators of graft-vs.-host disease (GVHD), responsible for T helper 1 (Th1) differentiation and T helper 17 (Th17) stabilization, respectively
The IL-12 family of cytokines can direct the donor immune response to execute a range of proinflammatory and immunosuppressive functions that are relevant in GVHD (Figure 1)
Summary
Allogeneic hematopoietic cell transplantation (allo-HCT) is performed with curative intent for high-risk blood cancers and bone marrow failure syndromes. Tissue damage from pre- transplant conditioning regimens results in a prolonged (up to 12 weeks post allo-HCT) increase of various cytokines; these include interleukin 1β (IL-1β), interleukin 6 (IL-6), interleukin 8 (IL-8), interleukin 10 (IL-10), interleukin 12 (IL-12), interleukin 21 (IL-21), interleukin 23 (IL-23), transforming growth factor β (TGFβ), and tumor necrosis factor α (TNFα) [9,10,11] These cytokines are primarily produced by activated dendritic cells (DCs) in response to tissue damage and microbe exposure, in concert with release of damage associated molecular patterns (DAMPs), including high mobility group protein B1 (HMGB-1) and adenosine triphosphate (ATP), as well as pathogen associated molecular patterns (PAMPs), which include lipopolysaccharide (LPS) and peptidoglycan. Strategies for protecting/promoting prompt repair of target tissues may reduce GVHD severity
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