Graft-versus-host disease and the Th1/Th2 paradigm

Abstract

Graft-versus-host disease (GVHD) is the major complication after allogeneic bone marrow transplantation (BMT) and is initiated by alloreactive donor T cells recognizing foreign histocompatibility antigens of the host. There is now substantial experimental and clinical evidence to implicate a dysregulation of cytokine networks as a primary cause for the induction and maintenance of GVHD. In this article, current knowledge of the involvement of cytokines in GVHD is reviewed. The balance between type 1 cytokines (interleukin-2, interferon-gamma) and type 2 cytokines (interleukin-4, interleukin-10) is hypothesized to govern the extent to which a cell-mediated immune response and a systemic inflammatory response develop after allogeneic BMT. Because type 2 cytokines can inhibit the production of the proinflammatory cytokines interleukin-1 and tumor necrosis factor-alpha, a type 1 to type 2 shift in the initial response of donor T cells to host alloantigens may interrupt the cytokine cascade after allogeneic BMT and may offer a new approach to the prevention and treatment of acute GVHD. Interventions to specifically eliminate or modify the response of donor T cells to alloantigens in order to reduce GVHD may obviate the need for T cell depletion in clinical BMT and thus avoid the increased risk of relapse of malignancy and impairment of donor cell engraftment.

T Helper–Cell Phenotype Regulates Atherosclerosis in Mice Under Conditions of Mild Hypercholesterolemia

“…IFN-␥ upregulates IL-1 and TNF-␣ production, cytokines that are pivotal protein mediators of inflammation 24 and upregulate adhesion molecule expression on vascular endothelial cells. 25,26 Gupta et al, 27 using compound apoE-deficient, IFN-␥ receptor-deficient mice, showed that IFN-␥ can potentiate murine atherosclerosis through both local effects in the arterial wall and systemic effects on plasma lipoproteins. Conversely, Th2-derived IL-4 inhibits proinflammatory cytokine release.…”

“…Conversely, Th2-derived IL-4 inhibits proinflammatory cytokine release. 25 Alternatively, IA expression may allow the presentation of proatherogenic antigens, whereas IE does not. In any event, oxidized LDL, as suggested by others, should be considered an important candidate as the antigen responsible for T-cell activation.…”

Antagonist of Secondary Lymphoid-Tissue Chemokine (CCR Ligand 21) Prevents the Development of Chronic Graft-Versus-Host Disease in Mice

“…The histopathology of acute GVHD is characterized by mononuclear cell infiltrates and epithelial injury in target organs. The pathogenesis of acute GVHD involves the development of a Th1 type cell-mediated immune response in which IFN-␥ is thought to play a prominent role (8,9). In contrast, chronic GVHD has a more indolent course, and has more diverse pathologic manifestations.…”

Chronic GVHD and concurrent new-onset nephrotic syndrome in allogeneic transplant recipients. Incidence, pattern and therapeutic outcomes

“…In the experimental models of cGVHD, evidence of B-cell dysregulation is well described. [11][12][13] The kidney is a rare target organ in cGVHD, but the development of renal disease after allo-HCT occurring temporally with cGVHD suggests that the renal tubular system might be a potential cGVHD target. Resolution of proteinuria with anti-CD20 Ab in our and other series support the role of B-cell dysregulation in renal pathology as in other manifestations of cGVHD.…”