Immunological basis for treatment of graft versus host disease after liver transplant

Abstract

Graft versus host disease (GVHD) after liver transplant, although a rare disease, has a very high mortality rate. GVHD occurs due to immunoreactions caused by donor T lymphocytes and host cell surface antigens resulting in proliferation and clonal expansion of T lymphocyte. Migration of effector cells, including macrophages, NK cells and cytotoxic T lymphocyte, to the target organs such as skin, intestine and bone marrow results in skin rashes, diarrhea and bone marrow depression. GVHD is diagnosed by clinical symptoms, histopathological findings and by the presence of chimerism. The delayed diagnosis, opportunistic infections and lack of definitive treatment of post orthotopic liver transplant (OLT)-GVHD results in sepsis and multi-organ failure leading to very low survival rates. In this review, we have focused on early diagnosis and critically discuss novel treatment modalities to decrease the incidence of GVHD.

Keywords: Chimerism; Graft versus host disease; Immunoreactivity; Multi organ failure; Opportunistic infections; Sepsis; Surface antigens; T lymphocytes; liver transplant.

Figure 1

Schematic diagram showing pathogenesis of GVHD in liver transplant. The first phase includes mucosal damage of recipient due to chemotherapy, irradiation, infections or liver disease causing an influx of bacterial endotoxin like lipopolysaccharide (LPS) from the intestinal lumen into the blood. Macrophages secrete cytokines and chemokines, including interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-α) leading to up-regulation of major histocompatibility complex I and II (MHC-I, MHC-II) expression and adhesion molecules, which cause further increase in antigen presenting capacity. Association of antigen presenting cells (APCs) and donor T cells causes activation, proliferation and clonal expansion of T lymphocytes via cytokines like Interleukin-2 (IL-2) and Interleukin-12 (IL-12), and these activated T cells will further secrete IFN-gamma (IFN-γ) leading to proliferation of effector cells like natural killer cells (NK cells) and cytotoxic T lymphocytes (CTLs). These effector cells migrate to target organ and cause symptoms of GVHD. Both specific effector cells (CTL) and nonspecific effector cells (NK cells and macrophage) contribute to tissue damage. CTLs cause apoptosis through release of granzyme or perforins or by Fas-Fas ligand interaction [13].

Figure 2

Schematic diagram showing existing and potential novel treatment modalities for post-OLT GVHD. - Indicate negative regulatory role of the drug; Post-OLT GVHD-post-orthotropic liver transplant Graft versus Host Disease; IL (interleukin)-1, 2,12; TNF (tumor necrosis factor)-alpha; IFN (interferon)-gamma; TLRs-toll like receptors; NLRs- NOD-like receptors; DAMPs- damage associated molecular pattern; LPS-lipopolysaccharide; T-bet - T cell-Bromodomain and Extra-Terminal motif; OKT3-Purified Anti-human CD3 Antibody Anti-CD3; APC-antigen presenting cells; TCR-T-cell receptor; MHC- major histocompatibility complex. (For the description of mechanism of action of drugs and inhibitors, please see the text).