Treg-mediated immunomodulation is emerging as a promising therapeutic avenue for Graft-versus-Host Disease (GvHD). These therapies harness the ability of Tregs to induce stable immune tolerance.
Adoptive nTreg Therapy
Adoptive nTreg therapy involves isolating circulating nTregs from a donor. These cells are then infused fresh or expanded in vitro before being administered to the patient. Clinical trials have demonstrated the feasibility and safety of adoptive nTreg transfer in GvHD treatment. Refinements in manufacturing processes aim to increase product purity and cell numbers for clinical application.
nTreg Expansion Protocols
Several protocols have been developed to expand nTregs due to their naturally low numbers in peripheral blood. These protocols often use polyclonal stimuli and IL-2 to generate clinically relevant cell numbers. Phase I trials using umbilical cord blood-derived expanded nTregs show a favorable safety profile and hint at preventive activity against acute GvHD (aGvHD) without interfering with immunosurveillance.
Modulating Conventional T Cells into iTregs
An alternative strategy involves modulating conventional T cells into induced Tregs (iTregs) in vitro, exploiting endogenous mechanisms of Treg biology. iTregs generated with TGFb and rapamycin have shown a favorable profile in clinical evaluation. Efforts to induce allo-antigen-specific tolerance are also underway. Preclinical studies have demonstrated iTreg's ability to treat autoimmune diseases and prevent graft rejection.
Targeting Endogenous nTregs In Vivo
Another approach targets endogenous nTregs in vivo through cytokine modulation. Administering low-dose IL-2 has shown great responses in chronic GvHD (cGvHD) patients by promoting thymic differentiation and peripheral expansion of nTregs. Subsequent studies are expanding the application of low-dose IL-2 in cGvHD patients, with real-world data showing that it is safe and well-tolerated in children and young adults with steroid-refractory cGVHD.