Genetically modified immune cells show potential to prevent organ rejection

A proof-of-principle cell therapy that can “disarm” highly immune-sensitized patients before organ transplantation was presented in Frontiers in Immunology. The scientists engineered regulatory T cells (Treg) with a chimeric anti-HLA antibody receptor (CHAR) — essentially, with a “bait” of the HLA-A2 protein that turns on Tregs when in contact with B cells producing anti-HLA-A2 antibodies. In vitro, these CHAR-Tregs recognized and suppressed high-affinity IgG production in presensitized patients, while maintaining the “identity” of Tregs (FOXP3/HELIOS) and not killing the target cells. This provides a chance for targeted desensitization without total immunosuppression.

Background of the study

In transplantology, the main “conflict of interest” is antibodies against donor HLA antigens. After transfusions, pregnancies, or previous transplants, the recipient often develops sensitization: anti-HLA IgG and B-cell memory, ready to quickly “unfold,” are already circulating in the blood. Such patients are less compatible, wait longer for an organ, and have a higher risk of acute and chronic antibody rejection. Standard desensitization protocols (plasmapheresis/immunoadsorption, high doses of IVIG, rituximab, proteasome inhibitors, imlifidase) act broadly and roughly: they reduce the overall pool of antibodies or cells, but do not target specific “dangerous” clones and are accompanied by toxicity and infectious risks.

The immune system has its own "brake" - regulatory T cells (Treg), which maintain tolerance to "foreign". In recent years, Treg therapy has become a real clinical strategy, but in the "default" version it is non-selective: the injected cells do not distinguish which antigen the reaction is developing against. Therefore, researchers are trying to "screw on the target" - to equip Tregs with artificial receptors that are triggered only when they encounter the right signal. This is how the idea of chimeric receptors (similar in spirit to CAR technologies) arose, but assembled not on the basis of anti-CD19, but from the domains of the HLA molecules themselves, so that Tregs are activated near B cells producing the corresponding anti-HLA antibodies.

The critical requirements for such "targeted" Tregs are twofold. First, they must remain true Tregs (maintain FOXP3/HELIOS and suppressor programs), without breaking into the effector phenotype against the background of strong stimulation. Second, their action must be targeted: suppressing precisely allospecific B-clones and plasmablasts, minimally interfering with the rest of the immune system, so as not to raise the cost of treatment with infections and tumor risks. If this problem is solved, a method for soft, pinpoint desensitization before transplantation and reducing the need for total immunosuppression after it will appear.

Finally, a practical context: in some patients, sensitization is directed to one or two “problematic” alleles (e.g., HLA-A2), and it is these that block access to organs. Cell therapy targeting such “bottlenecks” can expand the pool of compatible donors, speed up transplantation, and reduce the incidence of antibody rejection - especially in children and in recipients with long-term “historical” contact with foreign HLA (multiple transfusions, repeated transplants). Therefore, proof of principle for anti-HLA-induced Tregs is an important step towards personalized immunomodulation in transplantology.

How the new cell is structured

• Construction: extracellular domain of HLA-A2 + hinge CD8 + transmembrane CD28 + signaling "tandem" CD28-CD3ζ. This receptor is activated when there is an anti-HLA-A2 antibody on the surface of the B-cell.
• Specificity: CHAR-Treg “start” specifically on anti-A2 B-cells, without affecting other immunity.
• Safe Treg profile: after activation, they do not lose line markers (FOXP3, HELIOS), i.e. they remain “brakes” and do not turn into “gas”.
• Non-cytotoxic: Unlike modified conventional CD4 T cells with the same receptor, CHAR-Treg do not kill anti-A2 cells, but suppress their function.

What exactly was checked?

• Ex vivo patient model: HLA-A2 presensitized patients' blood mononuclear cells were primed with stimuli (HLA-A2-K562), then CHAR-Treg were added and IgG (ELISA) and B-cell composition (spectral flow cytometry, UMAP) were measured.
• Result: after 48 hours and 5 days, IgG production was significantly reduced (in 2 of 3 patient samples), the proportion of B cells in general decreased without an obvious “choice” between subtypes (naive, memory, marginal zone, plasmablasts).
• Authors' interpretation: The sensitivity of the assay can be increased by anti-A2-specific ELISA and separate assessment of IgG classes; testing in a larger number of patients and for other HLA alleles (e.g. A24) is needed.

Why is this important for transplantation?

Today, 20% of primary and up to 75% of repeat recipients already have anti-HLA antibodies, which dramatically narrows the pool of suitable donors and pushes for high doses of immunosuppression. Non-selective desensitization protocols (plasmapheresis, B-cell “zeroing”) do not work smoothly and are fraught with complications - from infections to nephro- and neurotoxicity (especially in children). Targeted Tregs, acting only against “dangerous” B-clones, theoretically allow for expanded access to organs and reduced overall toxicity after transplantation.

• Key potential benefits:
  • Before transplantation: “remove” sensitization to a specific HLA and make the patient comparable to a non-sensitized patient.
  • Post-transplant: reduce doses of basic immunosuppression and risks of chronic antibody rejection.
  • Beyond transplantation: The approach has potential applications in HCV and even in cases of miscarriage where the mother develops antibodies to the father's HLA.

What the authors themselves and press reports say

The MUSC team (USA) calls the work “the first step toward targeted immunosuppression: suppressing precisely those B cells that threaten the transplant, while leaving the rest of the immune system alone.” The release emphasizes the potential to reduce side effects and “level the playing field” for those who are currently almost impossible to transplant due to severe sensitization.

Where are the boundaries and what's next?

• This is an in vitro/ex vivo proof of principle on a small number of patient samples: it is too early to talk about the clinic. First human trials, validation for different HLAs and in-depth mechanistics (secreted factors, contact-dependent suppression, CHAR-Treg transcriptomics) are needed.
• It is important to work out specificity and safety: to make sure that suppression is strictly antigen-directed and does not disrupt other branches of immunity.

What to remember

• Tregs engineered with HLA-A2 “bait” recognize and suppress B cells that are dangerous to the transplant.
• In vitro, they reduce IgG production in sensitized patients and maintain the stability of the Treg phenotype without cytotoxicity.
• This is a targeted alternative to non-selective desensitization, with the potential to reduce immunosuppression doses and expand access to transplants. The next step is clinical trials.

Source: Valentín-Quiroga J. et al. Chimeric anti-HLA antibody receptor engineered human regulatory T cells suppress alloantigen-specific B cells from pre-sensitized transplant recipients. Frontiers in Immunology, published 15 August 2025. DOI: 10.3389/fimmu.2025.1601385