In 1986, Mosmann and Coffman observed that individual CD4+ T helper (Th*) cell clones express phenotypically distinct cytokine profiles, thereby giving rise to a unifying concept “the Th1/Th2 paradigm”(Fig. 1)(1). Central to this paradigm is the role of certain cytokines which act as cross-regulators of Th1/Th2 cell function. Interferon-γ (IFNγ), a Th1 product, inhibits expression of the Th2 program, whereas interleukin (IL) 4 and IL-10, Th2 products, can act to block the Th1 program. Moreover, polarized cytokine programs (ie, Th1+ and Th2-or Th1-and Th2+) have been detected in vivo, most notably in murineLeishmania major infections (2). In appreciation of these facts, an intensive effort has been launched to reach an understanding of the CD4+ T-cell programs associated with allograft rejection and tolerance. Indeed, new therapeutic strategies based on the concept of manipulating cytokine networks have been espoused as a means to guide the allograft response toward a tolerant state (Fig. 1). These strategies include:(a) inhibition of production/effects of Th1 cytokines, and (2) enhancement of systemic or local levels of Th2 cytokines.

Recently it has become apparent that the Th1/Th2 model, while providing a valuable framework for probing various models, has undoubtedly oversimplified the complexity of cytokine responses by individual T cells in vivo (3, 4). Indeed, as suggested by Mosmann and Kelso, these two patterns of cytokine expression likely represent extremes of many possible outcomes. The aim of this Overview is to consider the cytokine programs associated with allograft rejection and tolerance in the light of recent studies that highlight two important phenomena: first, the redundancy of cytokines able to act as T-cell growth factors; second, the pleiotropic nature of individual cytokines. It is with the characteristics of redundancy and pleiotropism in mind that we consider whether the manipulation of specific cytokine pathways provides a robust opportunity for inducing transplantation tolerance in the clinic.