Novel approaches are needed for GVHD prophylaxis and therapy. Naive CD4+ T cells differentiate into distinct lineages (Th1, Th2, Th17, Treg) under the influence of APCs and specific cytokine programs. Data suggest unique contributions of these CD4+ T-cell subsets to the target manifestations of GVHD. 1 Donor Th1 CD4+ T cells have a central role in the pathogenesis of acute GVHD, and preclinical data have demonstrated that neutralization of IL-12 prevented the development of acute GVHD, polarized CD4+ cells toward a Th2 phenotype and provided longterm protection from GVHD in mice. 2 Th17 cells have been implicated in solid organ allograft rejection and autoimmunity, and emerging evidence demonstrates their role in the pathogenesis of acute GVHD. In murine transplantation models, Th17 cells infiltrated target organs and were sufficient for the generation of GVHD. 3–5 In addition, secretion of IL-23 by APCs is an essential component of GVHD induction, 6 indicating the relevance of this cytokine, in particular, as a therapeutic target. Thus, inhibition of both Th1 and Th17 CD4 differentiation programs may provide a powerful novel approach to GVHD control. 2–10 Ustekinumab (Stelara; Centocor Inc, Malvern, PA, USA) is a human, Ig G1-k MoAb, which binds the p40 subunit shared by the cytokines IL-12 and IL-23. Given the activity of this agent in allied immune-mediated disorders, there is a rationale to neutralize p40 in the prevention or therapy of GVHD.

A 39-year-old woman with severe aplastic anemia underwent an unrelated (mismatched at one HLA-A allele) transplant on a phase II clinical protocol of GVHD prevention, using humanized anti-CD3 Ab visilizumab, tacrolimus and MTX (clinicaltrial. gov NCT00720629). By day+ 28 post HCT, she had biopsy-confirmed acute GVHD, covering approximately 70% body surface area, which was refractory to 2 mg/kg/day of prednisone, topical triamcinolone 0.1% cream and multiple lines of rescue therapy (Figure 1a). Beyond the first line therapy with systemic and topical glucocorticoids and continuation of tacrolimus, the following additional systemic immune suppressive therapies were utilized in an effort to achieve GVHD control: sirolimus (week 3 from GVHD onset, maintained at therapeutic serum levels thereafter); extracorporeal photopheresis (week 3, thereafter performed biweekly for duration of follow-up); mycophenolate mofetil (started on week 6, continued thereafter); and psoralen and ultraviolet A therapy (PUVA)(started on week 6, performed three times weekly thereafter). During week 19 of ongoing GVHD therapy, she was treated with usteki-