Transitional B-cell Cytokines Risk Stratify Early Borderline Rejection After Renal Transplantation
Cherukuri A, Abou-Daya K, Chowdhury R, et al. Kidney Int. 2023;103:749–761.
A common histological finding in renal transplant biopsies is mild allograft inflammation that does not meet the threshold for classification as acute rejection (AR), often termed “borderline rejection” (BL).1 Most patients with BL can go on to achieve excellent long-term outcomes; however, a smaller subset are at risk of developing more extensive inflammation and early graft loss without intervention. There is currently no consensus on best management for these patients, presenting a clinical dilemma given the risks of unnecessary escalation of immunosuppression.
The identification of noninvasive biomarkers that may provide insight into the status of an allograft has long been sought after. The authors of this study present a case for accurate identification of BL patients at risk of early graft loss through analysis of transitional-1 B (T1B)-cell cytokine expression. A reduction in the ratio of transitional B-cell expression of interleukin 10 (IL-10) to tumor necrosis factor alpha (TNF-α), thought to represent a surrogate measure of proinflammatory to regulatory B-cell polarization, has previously been associated with renal allograft injury and prediction of outcomes.2,3
Cherukuri and coworkers analyzed a cohort of 851 renal allograft recipients with graft biopsies within 4 mo of transplantation followed over a 7-y period. Patients with BL (n = 217) or no significant inflammation (NI) (n = 387) on this early biopsy were compared. Analysis of clinical characteristics and histological findings did not contribute in risk stratifying the BL group. Of the clinical characteristics collected, only female gender and basiliximab induction were independent risk factors for BL by multivariate logistic regression.
Flow cytometric analysis of PBMC at 3 mo posttransplant, from 158 patients with NI (n = 105) or BL (n = 53) on early biopsies, revealed a correlation between the T1B cell frequency, ratio of T1B IL-10/TNF-α, and long-term outcomes. Although a 4-fold reduction in the frequency of circulating T1B cells was identified in BL patients who later developed AR, the T1B IL-10/TNF-α ratio was the most effective parameter for risk-stratifying these patients, yielding a receiver operating characteristic area under the curve (ROC-AUC) of 0.87 (95% CI, 0.72-1.00; P < 0.0001). A ratio of 1.3 was deemed the optimal cut-off value, with a negative predictive value of 91% and positive predictive value of 86% for the prediction of development of late AR.
These findings indicate that the serum T1B IL-10/TNF-α ratio may represent a promising candidate for a noninvasive biomarker in this important subset of patients. If validated, this measure would enable early identification and immunosuppression escalation for patients at risk of progression to AR while avoiding unnecessary treatment of patients with a good prognosis.
Selective Bcl-2 Inhibition Promotes Hematopoietic Chimerism and Allograft Tolerance Without Myelosuppression in Nonhuman Primates
Sasaki H, Hirose T, Oura T, et al. Science Transl Med. 2023;15:eadd5318.
Hematopoietic stem cell transplantation (HSCT), the standard of care for several hematological malignancies, has been evaluated in other contexts such as autoimmune disease and induction of transplant tolerance.1 It is widely understood that mixed chimerism can induce tolerance to solid organ transplants; however, the conditioning protocols required for successful HSCT, such as total body irradiation (TBI) or chemotherapy regimens, carry significant toxicity including pancytopenia, life-threatening infections, and late secondary malignancy. These adverse effects represent profound limitations preventing wider adoption of HSCT in nonmalignant contexts.
In this study, Sasaki and coworkers describe a method of selective inhibition of B-cell lymphoma 2 (Bcl-2) for induction of chimerism without nonspecific myelosuppression. The Bcl-2 inhibitor venetoclax was evaluated in a nonhuman primate (NHP) model of combined HSCT and renal transplantation, aiming to establish its efficacy for induction of mixed chimerism and renal allograft tolerance.
Although selective Bcl-2 inhibition with venetoclax effectively induced the required peripheral leukocyte apoptosis, and partial bone marrow HSC depletion, treatment was not sufficient to establish chimerism without TBI. Notably, the TBI dose could be reduced by 50% when combined with Bcl-2 inhibition while still reliably achieving chimerism, without incidences of pancytopenia. As previously observed, Bcl-2 inhibition preferentially deleted conventional T cells, whereas regulatory T cells (Treg), which are less dependent on Bcl-2 for survival,2,3 were relatively spared.
Promotion of mixed chimerism by venetoclax achieved superior long-term (>300 d) immunosuppression-free allograft survival compared to TBI alone without Bcl-2 inhibition, and Bcl-2 inhibition alone. The authors attributed this finding to the high degrees of lymphoid chimerism achieved, and enrichment of Treg post–venetoclax treatment.
For a combined HSCT and solid organ approach to be clinically viable, it must at least prove noninferior to current patient and allograft survival outcomes with standard-of-care. This study demonstrates that induction of graft-protective chimerism is possible with a less stringent conditioning approach, improving the feasibility of HSCT-induced chimerism as a viable mechanism of inducing transplant tolerance. Importantly, venetoclax has regulatory approval, increasing the translational potential of these findings.
1. Filippone E, Farber J. The histological spectrum and clinical significance of T cell-mediated rejection of kidney allografts. Transplantation. 2023;107:1042–1055.
2. Cherukuri A, Rothstein DM, Clark B, et al. Immunologic human renal allograft injury associates with an altered IL-10/TNF-α expression ratio in regulatory B cells. J Am Soc Nephrol. 2014;25:1575–1585.
3. Cherukuri A, Salama AD, Mehta R, et al. Transitional B cell cytokines predict renal allograft outcomes. Sci Transl Med. 2021;13:eabe4929.
1. Messner F, Etra J, Dodd-O JM, et al. Chimerism, transplant tolerance, and beyond. Transplantation. 2019;103:1556–1567.
2. Ludwig LM, Hawley KM, Banks DB, et al. Venetoclax imparts distinct cell death sensitivity and adaptivity patterns in T cells. Cell Death Dis. 2021;12:1005.
3. Pierson W, Cauwe B, Policheni A, et al. Antiapoptotic Mcl-1 is critical for the survival and niche-filling capacity of Foxp3+ regulatory T cells. Nat Immunol. 2013;14:959–965.