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Polymorphisms of cytokine and innate immunity genes and GVHD

https://doi.org/10.1016/j.beha.2008.03.004Get rights and content

In the last 10 years, non-HLA genotypes have been investigated for their potential roles in the occurrence and severity of graft-versus-host disease (GVHD) as well as for their contribution to overall transplant-related mortality, infectious episodes, and overall survival. This chapter will review the latest results of cytokine gene polymorphisms between patient and donor which may cause the production of high or low levels of cytokines during the three-stage process of the GVHD ‘cytokine storm’. More recent investigations into innate immunity and the interaction with subsequent downstream cytokine production and ultimate tissue damage are discussed. The potential of these non-HLA genetics to aid in predicting GVHD and post-transplant survival and the relevance of this information to the clinic are reviewed.

Section snippets

Inflammatory cytokines and innate immune responses

Standard conditioning regimens which include total body irradiation (TBI) give rise to release of inflammatory cytokines including tumour necrosis factor α (TNFα) and interleukins 1 and 6 (IL-1 and IL-6).*1, *2 Release of these inflammatory cytokines into the patient's serum during conditioning has been correlated with an increased risk of more severe GVHD and poorer survival, whereas increased production of IL-10, a potent anti-inflammatory cytokine, seemed to be protective.*1, *3 In addition,

Phase 2 of GVHD: T-cell activation and chemokines

The second phase of GVHD involves activation of donor T cells via patient and donor APCs and release of Th1-type cytokines, especially IL-2 and interferon γ (IFNγ). Th2-type cytokines, such as IL-4, IL-5, IL-10 and IL-13, have also been described as modulating or exacerbating GVHD responses. Several SNP or microsatellite mutations also exist for these cytokine genes, and several have been studied with regard to HSCT outcome.

Effector-cell target organ damage

In the third phase of GVHD, cytotoxic effector cells as well as cytokines cause target-cell damage to the skin, gut and liver. In particular, cytotoxic T cells using the Fas and perforin pathways, together with NK cells and soluble TNF induced either by LPS-primed macrophages or donor T cells, cause damage, especially in the epithelial cells of the gut. IFNγ may sensitize both macrophages and epithelial cells and thus contribute to amplification of the cytotoxic response. Therefore, SNPs

Summary

In spite of the numerous reports, assessment of non-HLA genetics in relation to occurrence of acute and chronic GVHD has not yet been consistent between different cohorts of patients and donors. These limitations result from heterogeneity of clinical cofactors and treatment strategies, but should be overcome by large prospective analyses in homogeneous cohorts of transplants. Although the role of non-HLA markers in HSCT outcome is still not fully defined, there is no doubt that some of the

Acknowledgements

The authors wish to acknowledge support for their non-HLA genetics studies from the following European Commission grants: EUROBANK, contract no 2000 00 010; TRANSEUROPE, contract no QLK3-CT-2002-01936; TRANS-NET, contract no MRTN-CT-2004-512253; STEMDIAGNOSTICS, contract no LSHB-CT-2007-037703.

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