Low dose post-transplant cyclophosphamide and sirolimus induce mixed chimerism with CTLA4-Ig or lymphocyte depletion in an MHC-mismatched murine allotransplantation model

Mariama D Kabore; Corbin C McElrath; Mohamed A E Ali; Katherine Almengo; Arunakumar Gangaplara; Cameron Fisher; Mauricio A Barreto; Ahmad Shaikh; Purevdorj B Olkhanud; Xin Xu; Deanna Gaskin; Maria Lopez-Ocasio; Ankit Saxena; J Philip McCoy; Courtney D Fitzhugh

doi:10.1038/s41409-024-02237-y

Low dose post-transplant cyclophosphamide and sirolimus induce mixed chimerism with CTLA4-Ig or lymphocyte depletion in an MHC-mismatched murine allotransplantation model

Bone Marrow Transplant. 2024 Feb 12. doi: 10.1038/s41409-024-02237-y. Online ahead of print.

Authors

Mariama D Kabore^#¹, Corbin C McElrath^#¹, Mohamed A E Ali^#¹, Katherine Almengo¹, Arunakumar Gangaplara^{1

2}, Cameron Fisher¹, Mauricio A Barreto¹, Ahmad Shaikh^{1

3}, Purevdorj B Olkhanud¹, Xin Xu¹, Deanna Gaskin¹, Maria Lopez-Ocasio⁴, Ankit Saxena⁴, J Philip McCoy⁴, Courtney D Fitzhugh⁵

Affiliations

¹ Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
² Miltenyi Biotec, Gaithersburg, MD, 20878, USA.
³ Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia.
⁴ Flow Cytometry Core, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
⁵ Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA. courtney.fitzhugh@nih.gov.

^# Contributed equally.

PMID: 38347187
DOI: 10.1038/s41409-024-02237-y

Abstract

Allogeneic hematopoietic cell transplantation (allo-HCT) offers a curative option for patients with certain non-malignant hematological diseases. High-dose post-transplant cyclophosphamide (PT-Cy) (200 mg/kg) and sirolimus (3 mg/kg), (HiC) synergistically induce stable mixed chimerism. Further, sirolimus and cytotoxic T lymphocyte-associated antigen-4 immunoglobulin (CTLA4-Ig), also known as Abatacept (Aba), promote immune tolerance and allograft survival. Here, in a major histocompatibility complex (MHC)-mismatched allo-HCT murine model, we combined Aba and/or T-cell depleting anti-Thy1.2 (Thy) with a lower dose of PT-Cy (50 mg/kg) and Sirolimus (3 mg/kg), (LoC). While mice in the LoC group showed graft rejection, the addition of Thy to LoC induced similar donor chimerism levels when compared to the HiC group. However, the addition of Aba to LoC led to graft acceptance only in younger mice. When Thy was added to the LoC+Aba setting, graft acceptance was restored in both age groups. Engrafted groups displayed significantly reduced frequencies of recipient-specific interferon-γ-producing T cells as well as an increased frequency in regulatory T cells (Tregs) except in the LoC+Aba group. Splenocytes from engrafted mice showed no proliferation upon restimulation with Balb/c stimulators. Collectively, in combination with Aba or Thy, LoC may be considered to reduce graft rejection in patients who undergo allo-HCT.