Donor Stem Cell Infusions Fail to Induce Kidney Transplant Tolerance and May Sensitize
A dual human-primate trial finds donor MSC infusions are safe but do not establish chimerism or tolerance, and may trigger rejection-causing antibodies.
Summary
Two concurrent studies—one in rhesus macaques, one in six human kidney transplant recipients—tested whether monthly infusions of donor-derived mesenchymal stromal cells (MSCs) could promote immune tolerance and allow immunosuppression withdrawal. All participants received depletional induction plus belatacept and sirolimus maintenance. MSC infusions were acutely well-tolerated in both species. However, donor chimerism was never detected, and operational tolerance was never achieved. In a troubling subset, the MSC infusions appeared to act as a sensitizing stimulus: two of five NHPs receiving MSCs rejected their grafts on belatacept monotherapy with detectable donor-specific antibodies (DSA), and two of four human participants developed de novo DSA or borderline rejection that prevented or reversed immunosuppression withdrawal. The trial was terminated before the third dosing cohort began.
Detailed Summary
Kidney transplant recipients face lifelong immunosuppression, primarily with calcineurin inhibitors (CNIs) that carry serious long-term risks including nephrotoxicity, cardiovascular disease, infection, and malignancy. Costimulation blockade with belatacept combined with mTOR inhibition (sirolimus) offers a CNI-free alternative, but tolerance—where the immune system accepts the graft without any drugs—remains elusive. Mesenchymal stromal cells (MSCs) derived from donor bone marrow have immunomodulatory properties and were hypothesized to bridge the gap toward full tolerance, particularly during the lymphocyte repopulation window following depletional induction.
Two independent but concurrent studies were designed to test this hypothesis. In the nonhuman primate (NHP) arm, 15 rhesus macaques received MHC-mismatched kidney transplants and were divided into three groups: a control group (rhATG + belatacept + sirolimus), a thymic irradiation (TI) group, and a TI-plus-monthly-donor-MSC group. Sirolimus was withdrawn at six months and belatacept at one year. In the human arm—the ITN062ST TEACH trial—six adult recipients of live-donor kidney transplants received alemtuzumab induction and belatacept/sirolimus maintenance; four received 12 monthly donor MSC infusions with planned immunosuppression withdrawal if eligible.
Across both studies, MSC infusions were acutely safe and well-tolerated, with no infusion reactions or acute renal deterioration. However, neither study achieved its primary goal. In the NHP model, no survival advantage was observed across the three groups. Control and TI animals were successfully weaned to belatacept monotherapy but ultimately rejected once fully off immunosuppression. More concerning, two of the five MSC-treated NHPs rejected while still on belatacept monotherapy—earlier and more aggressively—in association with the development of DSA against donor MSCs and donor lymphocytes. In vitro data showed that donor MSCs upregulate MHC class II molecules and the co-stimulatory molecule CD40 under inflammatory conditions (IFN-γ and TNF-α stimulation), providing a mechanistic basis for antibody-mediated sensitization.
In the human TEACH trial, two of four MSC-treated patients could not initiate immunosuppression withdrawal due to de novo DSA or borderline rejection findings on protocol biopsy. The two patients who did attempt withdrawal both experienced rejection episodes, though these were reversible with treatment. No patient achieved the primary endpoint of operational tolerance 52 weeks after completing immunosuppression withdrawal. The trial was halted before enrolling the highest-dose cohort.
The findings carry important implications: donor MSCs, at least as administered here (monthly IV infusions without thymic irradiation in humans), do not engraft, do not establish chimerism, and do not meaningfully shift the immune system toward tolerance. In a subset of recipients, they may actually worsen outcomes by acting as repeated antigenic stimuli that drive donor-specific antibody formation. The authors suggest that inflammatory conditions in the post-transplant environment may convert MSCs from immunosuppressive agents into immunogenic ones, a phenomenon with relevance to other cell-therapy approaches in transplantation.
Key Findings
- Monthly donor MSC infusions were acutely safe in both humans and rhesus macaques with no infusion reactions observed.
- Donor chimerism was undetectable and operational tolerance was not achieved in either the primate or human studies.
- 2 of 5 NHPs receiving MSCs developed donor-specific antibodies and rejected on belatacept monotherapy—earlier than controls.
- 2 of 4 human MSC recipients developed de novo DSA or borderline rejection, blocking immunosuppression withdrawal.
- Donor MSCs upregulate MHC class II and CD40 under inflammatory cytokine stimulation, suggesting a sensitization mechanism.
Methodology
Two concurrent controlled studies: a 15-animal rhesus macaque kidney transplant model with three arms (control, thymic irradiation, TI plus monthly donor MSC infusion) and a Phase I open-label dose-escalation human trial (ITN062ST TEACH, NCT03504241) enrolling six live-donor kidney recipients with alemtuzumab induction and belatacept/sirolimus maintenance, four of whom received 12 monthly donor MSC infusions. Both studies used depletional induction and planned sequential immunosuppression withdrawal as the tolerance-assessment endpoint.
Study Limitations
Small sample sizes in both studies limit statistical power and generalizability. Thymic irradiation was used in the NHP but not human arm, making direct cross-species comparison imperfect. The human trial was terminated before the highest dose cohort was enrolled, leaving the dose-response question unanswered.
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