Ben Afzali

The role of T helper 17 (Th17) and regulatory T cells (Treg) in human organ transplantation and autoimmune disease

Uncommitted (naive) murine CD4+ T helper cells (Thp) can be induced to differentiate towards T helper 1 (Th1), Th2, Th17 and regulatory (Treg) phenotypes according to the local cytokine milieu. This can be demonstrated most readily both in vitro and in vivo in murine CD4+ T cells. The presence of interleukin (IL)‐12 [signalling through signal transduction and activator of transcription (STAT)‐4] skews towards Th1, IL‐4 (signalling through STAT‐6) towards Th2, transforming growth factor (TGF)‐β towards Treg and IL‐6 and TGF‐β towards Th17. The committed cells are characterized by expression of specific transcription factors, T‐bet for Th1, GATA‐3 for Th2, forkhead box P3 (FoxP3) for Tregs and RORγt for Th17 cells. Recently, it has been demonstrated that the skewing of murine Thp towards Th17 and Treg is mutually exclusive. Although human Thp can also be skewed towards Th1 and Th2 phenotypes there is as yet no direct evidence for the existence of discrete Th17 cells in humans nor of mutually antagonistic development of Th17 cells and Tregs. There is considerable evidence, however, both in humans and in mice for the importance of interferon (IFN)‐γ and IL‐17 in the development and progression of inflammatory and autoimmune diseases (AD). Unexpectedly, some models of autoimmunity thought traditionally to be solely Th1‐dependent have been demonstrated subsequently to have a non‐redundant requirement for Th17 cells, notably experimental allergic encephalomyelitis and collagen‐induced arthritis. In contrast, Tregs have anti‐inflammatory properties and can cause quiescence of autoimmune diseases and prolongation of transplant function. As a result, it can be proposed that skewing of responses towards Th17 or Th1 and away from Treg may be responsible for the development and/or progression of AD or acute transplant rejection in humans. Blocking critical cytokines in vivo, notably IL‐6, may result in a shift from a Th17 towards a regulatory phenotype and induce quiescence of AD or prevent transplant rejection. In this paper we review Th17/IL‐17 and Treg biology and expand on this hypothesis.

Translational Mini-Review Series on Th17 Cells: Induction of interleukin-17 production by regulatory T cells

OTHER ARTICLES PUBLISHED IN THIS MINI‐REVIEW SERIES ON Th17 CELLSu2028Function and regulation of human T helper 17 cells in health and disease. Clin Exp Immunol 2009; doi:10.1111/j.1365‐2249.2009.04037.xu2028Are T helper 17 cells really pathogenic in autoimmunity? Clin Exp Immunol 2009; doi:10.1111/j.1365‐2249.2009.04039.xu2028CD4+ T helper cells: functional plasticity and differential sensitivity to regulatory T cell‐mediated regulation. Clin Exp Immunol 2009; doi:10.1111/j.1365‐2249.2009.04040.xu2028Development of mouse and human T helper 17 cells. Clin Exp Immunol 2009; doi:10.1111/j.1365‐2249.2009.04041.x

Intercellular Transfer of MHC and Immunological Molecules: Molecular Mechanisms and Biological Significance

The intercellular transfer of many molecules, including the major histocompatibility complexes (MHC), both class I and II, costimulatory and adhesion molecules, extracellular matrix organization molecules as well as chemokine, viral and complement receptors, has been observed between cells of the immune system. In this review, we aim to summarize the findings of a large body of work, highlight the molecules transferred and how this is achieved, as well as the cells capable of acquiring molecules from other cells. Although a physiological role for this phenomenon has yet to be established we suggest that the exchange of molecules between cells may influence the immune system with respect to immune amplification as well as regulation and tolerance. We will discuss why this may be the case and highlight the influence intercellular transfer of MHC molecules may have on allorecognition and graft rejection.

Helicobacter pylori induces in-vivo expansion of human regulatory T cells through stimulating interleukin-1β production by dendritic cells.

Helicobacter pylori is one of the most common infections in the world. Despite inciting inflammation, immunological clearance of the pathogen is often incomplete. CD4+CD25hiforkhead box protein 3 (FoxP3+) regulatory T cells (Tregs) are potent suppressors of different types of immune responses and have been implicated in limiting inflammatory responses to H.u2009pylori. Investigating the influence of H.u2009pylori on Treg function and proliferation, we found that H.u2009pylori‐stimulated dendritic cells (DCs) induced proliferation in Tregs and impaired their suppressive capability. This effect was mediated by interleukin (IL)‐1β produced by H.u2009pylori‐stimulated DCs. These data correlated with in‐vivo observations in which H.u2009pylori+ gastric mucosa contained more Tregs in active cell division than uninfected stomachs. Inciting local proliferation of Tregs and inhibiting their suppressive function may represent a mechanism for the chronic gastritis and carcinogenesis attributable to H.u2009pylori.

Vitamin d in renal transplantation

Recent developments in our understanding of vitamin D show that it plays a significant role in immunological health, uniquely occupying both an anti‐microbial and immunoregulatory niche. Vitamin D deficiency is widespread amongst renal transplant recipients (RTRs), thus providing one patho‐mechanism that may influence the achievement of a successful degree of immunosuppression. It may also influence the development of the infectious, cardiovascular and neoplastic complications seen in RTRs. This review examines the biological roles of vitamin D in the immune system of relevance to renal transplantation (RTx) and evaluates whether vitamin D repletion may be relevant in determining immunologically‐related clinical outcomes in RTRs, (including graft survival, cardiovascular disease and cancer). While there are plausible biological and epidemiological reasons to undertake vitamin D repletion in RTRs, there are few randomized‐controlled trials in this area. Based on the available literature, we cannot at present categorically make the case for routine measurement and repletion of vitamin D in clinical practice but we do suggest that this is an area in urgent need of further randomized controlled level evidence.

Vitamin D in Renal Transplantation - from Biological Mechanisms to Clinical Benefits: Vitamin D in Renal Transplant Recipients

Recent developments in our understanding of vitamin D show that it plays a significant role in immunological health, uniquely occupying both an anti‐microbial and immunoregulatory niche. Vitamin D deficiency is widespread amongst renal transplant recipients (RTRs), thus providing one patho‐mechanism that may influence the achievement of a successful degree of immunosuppression. It may also influence the development of the infectious, cardiovascular and neoplastic complications seen in RTRs. This review examines the biological roles of vitamin D in the immune system of relevance to renal transplantation (RTx) and evaluates whether vitamin D repletion may be relevant in determining immunologically‐related clinical outcomes in RTRs, (including graft survival, cardiovascular disease and cancer). While there are plausible biological and epidemiological reasons to undertake vitamin D repletion in RTRs, there are few randomized‐controlled trials in this area. Based on the available literature, we cannot at present categorically make the case for routine measurement and repletion of vitamin D in clinical practice but we do suggest that this is an area in urgent need of further randomized controlled level evidence.