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Ustekinumab demonstrates activity in glucocorticoid-refractory acute GVHD

Bone Marrow Transplantation volume 47, pages 747–748 (2012)Cite this article

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 pre-clinical data have demonstrated that neutralization of IL-12 prevented the development of acute GVHD, polarized CD4+ cells toward a Th2 phenotype and provided long-term 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, 4, 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, 3, 4, 5, 6, 7, 8, 9, 10 Ustekinumab (Stelara; Centocor Inc, Malvern, PA, USA) is a human, Ig G1-κ 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.

Correlative studies were performed on the patient’s samples 70 days before and 35 days following ustekinumab therapy. Serum cytokine levels, including total p40 (free or Ab-bound), were determined by ELISA assay (Quansys Biosciences, Logan, UT, USA). Following ustekinumab, circulating serum IL-12p40 was increased (Figure 1b). Serum IL-2, IL-4, IL-5, IL-10, IL-17, IL-23, IFN-γ, TNF-α were below detectable range, both pre- and post-therapy by this method. Absolute CD4+, CD8+ and Treg (CD4+, CD25+, CD127low) numbers were quantified from whole blood. CD4+ non-Tregs (165–19 cells/μL), CD8+ T cells (48–18/μL) and Tregs (2.09–1.37/μL) all decreased following ustekinumab. To assess T-cell cytokine profile, PBMCs were activated with phorbol IZ-myristate 13-acetate (PMA) (50 ng/mL), Ionomycin (500 ng/mL) and Golgi stop (BD Biosciences, San Jose, CA, USA; 0.7 μL/mL), and cultured at 37 °C, 5% CO2 for 5 h. Cells were then washed and stained with CD3, CD4, CD8, CD25, CD127, Foxp3, IL-4, IL-17 and IFN-γ antibodies. Although IFN-γ-positive cells decreased following therapy, those positive for FoxP3 and those producing IL-4 increased (Figure 1c). In the analysis of supernatant cytokines, PBMC were activated with PMA/Ionomycin as above. TNF-α, INF-γ and IL-2 decreased, whereas IL-4, IL-5, IL-10, IL-17 and TGF-β were not detectable (Figure 1d).

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References

  1. Yi T, Chen Y, Wang L, Du G, Huang D, Zhao D et al. Reciprocal differentiation and tissue-specific pathogenesis of Th1, Th2, and Th17 cells in graft-versus-host disease. Blood 2009; 114: 3101–3112.

    Article  CAS  Google Scholar 

  2. Williamson E, Garside P, Bradley JA, More IA, Mowat AM . Neutralizing IL-12 during induction of murine acute graft-versus-host disease polarizes the cytokine profile toward a Th2-type alloimmune response and confers long term protection from disease. J Immunol 1997; 159: 1208–1215.

    CAS  PubMed  Google Scholar 

  3. Carlson MJ, West ML, Coghill JM, Panoskaltsis-Mortari A, Blazar BR, Serody JS . In vitro-differentiated TH17 cells mediate lethal acute graft-versus-host disease with severe cutaneous and pulmonary pathologic manifestations. Blood 2009; 113: 1365–1374.

    Article  CAS  Google Scholar 

  4. Iclozan C, Yu Y, Liu C, Liang Y, Yi T, Anasetti C et al. T helper17 cells are sufficient but not necessary to induce acute graft-versus-host disease. Biol Blood Marrow Transplant 2010; 16: 170–178.

    Article  CAS  Google Scholar 

  5. Kappel LW, Goldberg GL, King CG, Suh DY, Smith OM, Ligh C et al. IL-17 contributes to CD4-mediated graft-versus-host disease. Blood 2009; 113: 945–952.

    Article  CAS  Google Scholar 

  6. Das R, Chen X, Komorowski R, Hessner MJ, Drobyski WR . Interleukin-23 secretion by donor antigen-presenting cells is critical for organ-specific pathology in graft-versus-host disease. Blood 2009; 113: 2352–2362.

    Article  CAS  Google Scholar 

  7. Paczesny S, Hanauer D, Sun Y, Reddy P . New perspectives on the biology of acute GVHD. Bone Marrow Transplant 2010; 45: 1–11.

    Article  CAS  Google Scholar 

  8. Welniak LA, Blazar BR, Murphy WJ . Immunobiology of allogeneic hematopoietic stem cell transplantation. Annu Rev Immunol 2007; 25: 139–170.

    Article  CAS  Google Scholar 

  9. Williamson E, Garside P, Bradley JA, Mowat AM . IL-12 is a central mediator of acute graft-versus-host disease in mice. J Immunol 1996; 157: 689–699.

    CAS  PubMed  Google Scholar 

  10. Yang YG . The role of interleukin-12 and interferon-gamma in GVHD and GVL. Cytokines Cell Mol Ther 2000; 6: 41–46.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported in part by NIH grants CA132197, AI082498, CA076292 (to CA).

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  1. Department of Blood and Marrow Transplantation, Moffitt Cancer Center, Tampa, FL, USA

    J Pidala, L Perez, F Beato & C Anasetti

  2. Department of Oncologic Sciences, College of Medicine, University of South Florida, Tampa, FL, USA

    J Pidala, L Perez & C Anasetti

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Pidala, J., Perez, L., Beato, F. et al. Ustekinumab demonstrates activity in glucocorticoid-refractory acute GVHD. Bone Marrow Transplant 47, 747–748 (2012). https://doi.org/10.1038/bmt.2011.172

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