Foxp3-expressing Regulatory T Cells Expanded With CD28 Superagonist Antibody Can Prevent Rat Cardiac Allograft Rejection

• Published in: The Journal of heart and lung transplantation Vol. 27; no. 4; pp. 362 - 371
• Main Authors: Kitazawa, Yusuke, PhD, Fujino, Masayuki, PhD, Sakai, Takatoshi, BS, Azuma, Haruhito, MD, PhD, Kimura, Hiromitsu, MD, Isaka, Yoshitaka, MD, PhD, Takahara, Shiro, MD, PhD, Hünig, Thomas, MD, PhD, Abe, Ryo, MD, PhD, Li, Xiao-Kang, MD, PhD
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.04.2008; Elsevier Science
• Subjects: Animals; Antibodies, Monoclonal - pharmacology; Biological and medical sciences; Blood Cells - metabolism; Cardiology. Vascular system; CD28 Antigens - immunology; Cell Proliferation - drug effects; Concanavalin A - pharmacology; Forkhead Transcription Factors - metabolism; Graft Rejection - prevention & control; Graft Survival - drug effects; Heart Transplantation; Interleukin-2 Receptor alpha Subunit - metabolism; Interleukins - metabolism; Isoantigens - pharmacology; Male; Medical sciences; Myocardium - metabolism; Myocardium - pathology; Postoperative Period; Rats; Rats, Inbred Strains; Surgery; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Surgery of the heart; T-Lymphocytes, Regulatory - drug effects; T-Lymphocytes, Regulatory - metabolism; T-Lymphocytes, Regulatory - pathology; Time Factors; Transplantation, Heterotopic; Heart; Graft(material); Immune response; Rat; Antibody; Rodentia; Transplantation; Homotransplantation; Phlebology; Prevention; Rejection; Vertebrata; Mammalia; Treatment; Surgery; Animal; T-Lymphocyte; Graft; Circulatory system; Cardiology; Transcription factor; Expansion
• ISSN: 1053-2498; 1557-3117
• DOI: 10.1016/j.healun.2008.01.004

Background It is well known that CD4+ CD25+ regulatory T (Treg) cells play a central role in the suppression of autoimmunity, inflammation and allograft rejection. Therefore, therapeutic agents that capable of enhancing the number and activity of this T-cell subset are highly desirable. Methods The present study was designed to investigate the effects of superagonistic CD28-specific monoclonal antibody (supCD28 MAb) on preferentially expanded rat naturally occurring CD4+ CD25+ Treg (nTreg) cells and its applicability in cardiac transplantation. Results A single administration of supCD28 MAb preferentially proliferated nTreg cells. The increase of Foxp3 expression and polarization toward a Th2 cytokine profile correlated with decreased production of interferon-γ and increased production of interleukin-4 and -10 in the expanded CD4+ CD25+ Treg subset, which was capable of suppressing CD4+ CD25− T-cell proliferation after purification. Furthermore, supCD28 MAb administration revealed that nTreg cells were preferentially proliferating in vivo and recruited into the grafts, resulting in significant prolongation of full MHC-mismatch cardiac graft survival. Conclusions Our data demonstrate that supCD28 MAb targets expansion of nTreg cells in vivo and maintains and enhances their regulatory functions, which represents a major advance toward the therapeutic use of polyclonally activated Treg cells as cellular therapy for treatment of allograft rejection.