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Urinary-derived human chorionic gonadotropin to induce tolerance and promote healing in steroid-refractory GvHD

Bone Marrow Transplantation volume 51, pages 142–143 (2016)Cite this article

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In 2014, Elmaagacli et al.1 described a series of 20 patients with moderate/severe steroid-refractory or intolerant chronic GvHD treated with a urinary-derived preparation of human chorionic gonadotropin (hCG), given as an immune modulator based on its known tolerizing effects during pregnancy.2 The hCG treatment was given as a low-dose (187.5 IU) daily SC injection and was well tolerated. Remarkably, in this series of heavily pre-treated patients with chronic GvHD (that is, the median number of prior therapies for chronic GvHD in this cohort was 4), 60% of patients showed an objective response after 8 weeks of hCG therapy. One of the most marked examples of response to therapy was a patient with severe gastrointestinal GvHD who demonstrated healing of diffusely inflamed colonic epithelium after treatment with hCG. Correlative studies indicated a sevenfold increase in peripheral blood mononuclear cell expression of indoleamine 2,3 dioxygenase and a doubling of serum interleukin-10 levels during the study. One patient underwent a longitudinal study of circulating regulatory T cells (Treg), and expansion of the Treg pool was noted with hCG treatment.

Although this study represents a shift away from immunosuppression towards induction of tolerance—a welcome paradigm shift—in the therapy of refractory GvHD, further studies are needed. For example, pharmacokinetics and pharmacodynamics studies should be performed to determine the optimal dosage to achieve the desired immunologic effects of hCG. Perhaps even more importantly, the contribution of the non-hCG constituents of the preparations should be assessed for their role in achieving responses. Urinary-derived preparations of hCG are not purified, isolated hormone. They contain biologically relevant concentrations of a number of immune modulatory cytokines and growth factors in addition to hCG. For example, we have identified high concentrations of epidermal growth factor (EGF) and several other growth factors, cytokines and chemokines in a commercially available preparation of urinary-derived hCG (Pregnyl, Merck, Kenilworth, NJ, USA) using a 38-multiplex cytokine array (Millipore, Billerica, MA, USA) on a Luminex instrument (Austin, TX, USA) in the University of Minnesota Cytokine Reference Laboratory (Table 1). The sample from a single lot was tested in duplicate. The urinary-derived preparation used in the Elmaagacli study (Choragon, Ferring, Kiel, Germany) is not available for clinical use in the United States. However, that preparation has been shown in a prior study to have a similarly high EGF content compared with Pregnyl when tested via a specific EGF immunoassay.3 To our knowledge, measurement of other immunoregulatory proteins using a multiplex cytokine array has not been performed on these preparations.

Table 1 Growth factors and cytokines detectable in a commercial preparation of urinary-derived human chorionic gonadotropin (Pregnyl, Merck)
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References

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Acknowledgements

This work was supported in part by the UMN Cytokine Reference Laboratory (AP-M), and the Masonic Cancer Center, University of Minnesota (SGH). We thank Michael Ehrhardt for expert technical assistance.

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  1. Department of Medicine, Blood and Marrow Transplant Program, University of Minnesota, Minneapolis, MN, USA

    S G Holtan

  2. Department of Pediatrics, Blood and Marrow Transplant Program, University of Minnesota, Minneapolis, MN, USA

    A Panoskaltsis-Mortari

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  1. S G Holtan
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Correspondence to S G Holtan.

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Holtan, S., Panoskaltsis-Mortari, A. Urinary-derived human chorionic gonadotropin to induce tolerance and promote healing in steroid-refractory GvHD. Bone Marrow Transplant 51, 142–143 (2016). https://doi.org/10.1038/bmt.2015.220

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