A proof of concept study: Human C48-placenta immunoregulatory factor is an effective, single therapeutic agent enabling allogeneic, nonmanipulated murine bone marrow transplantation

Moroz, Chaya; Traub, Leonid; Rabizadeh, Esther; Zahalka, Muayad A.

doi:10.1016/j.exphem.2009.06.002

« PreviousExperimental Hematology
Volume 37, Issue 9 , Pages 1121-1130, September 2009

A proof of concept study: Human C48-placenta immunoregulatory factor is an effective, single therapeutic agent enabling allogeneic, nonmanipulated murine bone marrow transplantation

Chaya Moroz
- Laboratory of Molecular Immunology, Felsenstein Medical Research Center, Rabin Medical Center, Beilinson Campus, Petach Tikva, Israel
- Offprint requests to: Chaya Moroz, Ph.D., Molecular Immunology Unit, Felsenstein Research Center, Rabin Medical Center, Beilinson Campus, Petach Tikva 49100, Israel
Leonid Traub
- Laboratory of Molecular Immunology, Felsenstein Medical Research Center, Rabin Medical Center, Beilinson Campus, Petach Tikva, Israel
Esther Rabizadeh
- Hemato-Oncology Laboratory, Felsenstein Medical Research Center, Rabin Medical Center, Beilinson Campus, Petach Tikva; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
Muayad A. Zahalka
- Laboratory of Molecular Immunology, Felsenstein Medical Research Center, Rabin Medical Center, Beilinson Campus, Petach Tikva, Israel

Received 5 May 2009; received in revised form 8 June 2009; accepted 9 June 2009. published online 18 June 2009.

Objective

Cloned placenta immunoregulatory ferritin (PLIF) contains a novel, nonferritin bioactive domain (C-48) with immunodulatory activity. We documented that treatment of whole human bone marrow cells with PLIF and its subcloned C48 proteins resulted in myeloid progenitor cell growth and differentiation and T-cell suppression via an effect on the cytokine network. We tested whether this differential effect supports allogeneic bone marrow transplantation with long-lasting tolerance without any further treatments.

Materials and Methods

Splenocyte-enriched C3H (H2^k) whole bone marrow was transplanted into C57Bl (H2^b) recipients after total body irradiation. Recipients were injected with recombinant C48 (3mg/kg, intraperitoneal) for 21 days or with glutathione S-transferase. Animals were monitored for survival, chimerism, and clinical signs of graft-vs-host disease (GVHD). Next, chimera whole bone marrow was transplanted to secondary myeloablated C57Bl (H2^b) hosts without treatment.

Results

Mice that received C48 treatment following allogeneic splenocyte-enriched bone marrow transplantation demonstrated full-donor chimerism without GVHD mortality, and normal blood cell counts in 75% of recipients. Secondary transplants from the full chimera to myeloblated C57Bl hosts showed 100% engraftment, no GVHD mortality, and no impairment in the long-term hematopoietic reconstitution potential. Allogeneic response of spleen cells from secondary chimeras against donor C3H (H2^k) and recipient C57Bl (H2^b) were similar to syngeneic response, whereas reactivity to third party (DBA H2^d) was significantly enhanced.

Conclusions

Findings of this study provide the proof of concept that C48—a novel, single, bifunctional therapeutic modality enabled successful allogeneic, unmanipulated bone marrow transplantation without GVHD, and with lasting specific tolerance.