A major challenge in the current practice of transplantation is the requirement for long term immunosuppression to prevent allograft rejection. Long term immunosuppression results in an increased risk of infection [1], malignancy [2], and other related toxicities including renal injury [3], diabetes mellitus [4], hypertension [5], and dyslipidemia [6]. Transplantation tolerance, an immunologic state in which a transplant recipient's immune system lacks a destructive immune response to cells of an allograft while retaining reactivity to other foreign cells and antigens, represents an alternative strategy to prevent allograft rejection without the need for long term immunosuppression [7].

Despite numerous reported strategies for achieving allograft tolerance in murine models, combining donor bone marrow transplantation (DBMT) with solid organ transplantation represents the only reproducible approach in non-human primates (NHPs) and humans [8]. Bone marrow cells transplanted along with an allograft results in either full chimerism (complete replacement of recipient hematopoietic cells with donor cells) [9] or mixed chimerism (coexistence of recipient and donor hematopoietic cells) [10]. Achieving either full or mixed chimerism can result in acceptance of the allograft, however mixed chimerism is safer due to its lower risk of graft versus host disease (GVHD) [11].

The immunologic mechanisms by which hematopoietic chimerism results in transplantation tolerance are not yet fully understood. It is likely that both central T cell deletion and peripheral T cell regulation are involved in this process (Fig. 1). Central tolerance occurs in the thymus where donor-reactive immature T cells (thymocytes) undergo negative selection, leading to their clonal deletion [12]. Peripheral tolerance involves the regulation of donor reactive immune cells in the periphery through development of regulatory immune cell populations, as well as anergy and peripheral deletion of donor reactive T cells [13]. An important aspect of both central and peripheral tolerance is donor antigen specificity, resulting in regulation of immune cells and responses specific to donor antigens while allowing for intact responses to other foreign antigens. Pre-clinical and mechanistic studies have demonstrated that cytokines, proteins that have a broad range of effects on the immune system, have a pivotal role for induction/maintenance of both central and peripheral tolerance [14,15]. Cytokines can be pro- or anti-inflammatory, and the balance of inflammatory and regulatory signals mediated by cytokines can push the system to be more tolerogenic or inflammatory, which in the context of transplantation can lead to allograft tolerance or allograft rejection respectively (key cytokines summarized in Table 1).

In this review, we will first introduce the role of cytokines in central tolerance, focusing on the cytokines involved in intra-thymic clonal deletion of donor reactive thymocytes. We will then discuss the role of cytokines in induction and maintenance of peripheral tolerance including their role in development and function of two major regulatory cell populations, regulatory T cells (Tregs) and immature dendritic cells (iDCs) (key immune cells summarized in Table 2). Next, we will review findings from pre-clinical experiments highlighting the role of several important tolerogenic cytokines including IL-2, IL-10 and TGF-β. Lastly, we will discuss cytokine release syndrome (CRS), a clinically significant side effect observed in our chimerism based kidney tolerance protocol.