Acute Allograft Rejection Research Articles

Cardiac MRI in Heart Transplantation: Approaches and Clinical Insights.

Orthotopic heart transplant (OHT) is a well-established therapy for end-stage heart failure that leads to improved long-term survival rates, with careful allograft surveillance essential for optimizing clinical outcomes after OHT. Unfortunately, complications can arise after OHT that can compromise the success of the OHT. Cardiac MRI is continually evolving, with a range of advanced techniques that can be applied to evaluate allograft structure and function. Understanding the unique features of cardiac MRI in OHT recipients, identifying findings suggestive of acute or chronic complications, and recognizing the limitations of this imaging modality are essential for accurate interpretation of cardiac MRI findings and subsequent clinical reporting. The authors address the anticipated postsurgical anatomy and functionality of the OHT. Emphasis is placed on the advanced functional and tissue characterization features that can be seen in the stable OHT recipient, including global longitudinal strain, late gadolinium enhancement, native T1 and T2 mapping, and extracellular volume fraction. Subsequently, the evidence for detection of acute cardiac allograft rejection with cardiac MRI comprehensive tissue characterization techniques and the role of quantitative myocardial perfusion for cardiac allograft vasculopathy screening are discussed, with reference to their comparative standard of reference screening tests, including endomyocardial biopsy, invasive coronary angiography, and myocardial rest and stress perfusion PET/CT. Cardiac MRI has been included in contemporary OHT management guidelines and therefore can be considered a complementary tool for allograft evaluation. The authors demonstrate the complementary role cardiac MRI can play in cardiac allograft surveillance, with clinical examples. ©RSNA, 2025 Supplemental material is available for this article. See the invited commentary by Agarwal in this issue.

Peripheral Blood Immune Profiling to Predict Acute Corneal Allograft Rejection.

Peripheral Blood Immune Profiling to Predict Acute Corneal Allograft Rejection.

Characterizing the urobiome and associated metabolic profiles during acute rejection in renal transplant patients: A pilot study.

Characteristic alterations in the urinary microbiome, or urobiome, are associated with renal transplant pathology. To date, there has been no direct study of the urobiome during acute allograft rejection. The goal of this study was to determine if unique urobiome alterations are present during acute rejection in renal transplant recipients. We performed shotgun metagenomic sequencing of 32 mid-stream urine samples obtained from 15 transplant recipients pre-transplant, 1- and 3-months post-transplant, and at time of rejection discovered with for-cause biopsy. Within individuals, there was a 40-60 % difference in urobiome composition from pre-to-post-transplant in both rejectors and non-rejectors. The taxa Ureaplasma was enriched in rejectors compared to non-rejectors. However, a greater number of microbial genes were enriched in non-rejectors compared to rejectors, except for genes associated with tetracycline resistance, the lysophosphatidic acid synthesis pathway, and tryptophanyl-tRNA synthetase. Together, our findings suggest that the urobiome is significantly altered post-transplant with certain taxa and/or microbial genes potentially associated with acute allograft rejection/inflammation.

Unintended Pregnancy After Kidney Transplantation

OBJECTIVE: To define risk factors, obstetric morbidity, and allograft outcomes associated with an unintended pregnancy after kidney transplant. METHODS: This is a retrospective cohort study of pregnancies in women after kidney transplantation enrolled in the Transplant Pregnancy Registry International with births between 1967 and 2019, with cohorts categorized as intended pregnancies and unintended pregnancies. The primary outcome was acute kidney rejection during pregnancy or by 6 weeks postpartum. Secondary outcomes included allograft loss, severe maternal morbidity, and neonatal composite morbidity. Multivariable logistic regression, Kaplan–Meier curves, and Cox proportional hazards regression models were performed, with adjustment for covariates pertinent to allograft function. RESULTS: Among 1,723 pregnancies of kidney transplant recipients, 1,081 (62.7%) were intended and 642 (37.3%) were unintended pregnancies. Risk factors for unintended pregnancy included younger age, Black race, nulliparity, chronic hypertension, and transplant from a deceased donor. Exposure to mycophenolate products (16.0% vs 5.7%) and termination (4.7% vs 0.4%) were more common in unintended pregnancies (P<.001). Unintended pregnancy was not associated with acute kidney rejection (2.3% vs 0.9%, adjusted odds ratio [AOR] 2.38, 95% CI, 0.91–6.30, P=.08). Unintended pregnancy was independently associated with allograft loss at 2 years from the end of pregnancy (8.1% vs 3.5%, AOR 2.27, 95% CI, 1.32–3.94, P=.003) but not allograft survival (adjusted hazard ratio 1.22, 95% CI, 1.00–1.49, P=.05). There were no differences in severe maternal morbidity (3.3% vs 3.6%) or neonatal composite morbidity (12.9% vs 14.3%) by pregnancy intention. CONCLUSION: Unintended pregnancy was not associated with acute kidney allograft rejection in the peripartum period, but it was associated with mycophenolate exposure and allograft loss at 2 years from pregnancy. The same social vulnerabilities that underlie difficulty in accessing reproductive care may be similarly important for transplant health. We recommend prepregnancy counseling and longitudinal follow-up of transplant recipients to reduce rates of unintended pregnancy and to optimize transplantation success over time.

Graft-derived extracellular vesicles transport miRNAs to modulate macrophage polarization after heart transplantation

Heart transplantation, a crucial intervention for saving lives of those with end-stage cardiac failure, often faces complications from acute allograft rejection. This study focuses on the intricate dynamics of immune cell interactions and specific communication pathways between organs, which are not yet well understood. Our study investigates this interplay using a murine heterotopic transplant model, using single-cell RNA sequencing to examine CD45+ immune cells from both the heart grafts and spleens. We conduct a comprehensive analysis focused on functional enrichment, cell trajectory, and interorgan communication in heart transplants, highlighting dynamic interactions between monocyte/macrophage subtypes that is mediated by extracellular vesicles (EVs). We use unsupervised clustering and elucidate the complex cellular interactions that influence allograft outcomes. Notably, we discovered that microRNA-363 and microRNA-709, carried by EVs from CD63+ graft macrophages, can induce M1 polarization within the recipient’s spleen via the Fcho2/Notch1 signaling pathway. These insights illuminate the nuanced immune responses during acute cardiac rejection and suggest that targeting EVs from graft-resident macrophages may offer a new strategy to mitigate transplant rejection.

Resolution of Acute Lung Allograft Rejection Detected by Probe-based Confocal Laser Endomicroscopy.

Resolution of Acute Lung Allograft Rejection Detected by Probe-based Confocal Laser Endomicroscopy.

Pembrolizumab in combination with LEnvatinib in participants with hepatocellular carcinoma before liver transplant as Neoadjuvant TherapY-PLENTY pilot study.

The high recurrent rate after liver transplantation (LT) remains a clinical challenge, especially for those exceeding the Milan criteria (MC) and with high RETREAT scores. Therefore, the authors aim to investigate whether neoadjuvant systemic therapy allows safely administered and effectively reduces post-LT recurrence for those patients. In this prospective, randomized, open-label, pilot study, patients with HCC exceeding the MC were randomly assigned to PLENTY or control group before LT. The primary endpoint of the study was the recurrence-free survival after LT. Twenty-two patients were enrolled and randomly assigned: 11 to the PLENTY group and 11 to the control group. The 30-month tumor-specific RFS was 37.5% in the PLENTY group and 12.5% in the control group. The 12-month tumor-specific RFS after LT was significantly improved in the PLENTY group (87.5%) compared to the control group (37.5%) ( P =0·0022). The objective response rate in the PLENTY group was 30 and 60% when determined by RECIST 1.1 and mRECIST, respectively. Six patients (60%) had significant tumor necrosis, including three (30%) who had complete tumor necrosis at histopathology. No acute allograft rejection after LT occurred in the PLENTY and Control group. Neoadjuvant pembrolizumab plus lenvatinib before LT appears to be safe and feasible, associated with significantly better RFS for patients exceeding the MC. Despite the limitations of small sample size, this is the first RCT to evaluate neoadjuvant PD-1 blockade combined with tyrosine kinase inhibitors in LT recipients, the results of this study will inform future research.

Association of Donor Vascular Endothelial Growth Factor Gene Polymorphism With Acute Renal Allograft Rejection.

Recipient's VEGF-A polymorphisms have been reported to be associated with the risk of acute allograft rejection. However, an association of the donor's VEGF-A gene polymorphism with rejection remained unelucidated till now. In this study, VEGF-A gene SNPs at nine loci were analyzed in 160 kidney donors and recipients with rejection (rejectors, n=80) and without rejection (non-rejectors, n=80). Blood VEGF-A mRNA, plasma VEGF level, and intragraft VEGF expression were also analyzed by RT-PCR, ELISA, and immunohistochemistry, respectively. On comparing between the donor and rejectors, the polymorphic genotypes of VEGF -634 C>G [GG genotype, p<0.0001; OR (95% CI) = 17.74 (5.16-60.96)]; VEGF -1154 G>A [AG genotype, p<0.0001, OR (95% CI)=16.07 (3.68-70.15)]; VEGF +936 C>T [CT genotype, p<0.0001, OR (95% CI)=178.64 (23.28-1370.9), and TT genotype, p<0.0001; OR (95% CI)=3149 (278.91-35553)]; VEGF -1455 T>C [CC genotype, p value=0.0464, OR (95% CI) = 3.13 (1.07-9.10)]; VEGF -2578 C>A [CA genotype, p=0.0426, OR (95% CI)=4.62 (1.03-20.59), and AA genotype, p value<0.0001, OR (95% CI) = 21.89 (4.94-97.04)]; VEGF -2549 18bp Insertion/Deletion [ID genotype, p value<0.0001, OR (95% CI)=27.27 (3.61-205.73) and DD genotype, p value<0.0001, OR (95% CI)=25.18 (3.30-191.89) were significantly associated with acute rejection risk. On comparing rejectors versus non-rejectors, GA genotype of VEGF -1190 G>A and TC genotype of VEGF -1455 T>C were associated with the risk of rejection. On comparing donor VEGF between rejectors and non-rejectors, CG genotype of VEGF -634 C>G, AG of VEGF -1154 G>A; GA of VEGF -1190 G>A were associated with rejection. The blood VEGF-A mRNA and plasma VEGF levels were higher in the rejectors group compared to non-rejectors. Besides the recipient's VEGF SNPS, the donor's VEGF SNPs are also associated with the risk of acute rejection and may be closely monitored in evaluation to determine the risk of rejection.

Immunomodulation of T cell-mediated alloimmunity by proximity to endothelial cells under the mammalian target of rapamycin blockade

Endothelial cells (ECs) are an initial barrier between vascularized organ allografts and the host immune system and are thus well positioned to initiate and influence alloimmune rejection. The mammalian target of rapamycin inhibitor rapamycin is known to inhibit T cell activation and attenuate acute allograft rejection. It also has numerous effects on ECs. We hypothesized that A mammalian target of rapamycin blockade might directly alter EC alloimmunogenicity and reduce alloimmune responses independent of its effects on T cell function. Here we report that rapamycin treatment modulates EC coinhibitory ligand expression and alters cytokine/chemokine production. It alters the EC transcriptome broadly associated with negative regulation of immune responses. Rapamycin-treated ECs suppress EC-specific T cell proliferation independent of programmed cell death 1/programmed death-ligand interaction and inhibit T cells responding to adjacent allogeneic cells in a contact-independent manner via secreted inhibitory mediators above 10 kDa. The T cell hyporesponsiveness induced by rapamycin-pretreated ECs was rescued by exogenous interleukin 2. Preexposing donor hearts to rapamycin improves the effect of B7 costimulation blockade in prolonging heart allograft survival in a major histocompatibility complex-mismatched mouse model. Our results indicate that rapamycin-treated ECs have reduced alloimmunogenicity and created a local, contact-independent environment that limits T cell alloreactivity via anergy induction and improves the efficacy of B7 costimulation blockade.

Walter Brendel and the dawn of transplantation research in Germany.

Walter Brendel was a physiologist who headed the Institut of Experimental Surgery at the University of Munich (LMU) from 1961 until 1989. His legendary career began with the development of an anti-human lymphocyte globulin (ALG) at his Institute during the late 1960s. The initial successful treatment of a small number of patients culminated in the co-treatment of the first successfully heart-transplanted patient in Capetown, South Africa (successful reversal with ALG of an acute allograft rejection). Walter Brendel was a pioneering personality whose work has laid a wide platform for the promotion of interdisciplinarily conducted innovative research programs in various domains of translational science and medicine. Among the many innovative achievements, the most notable are: discovery of involvement of the alternative pathway of complement activation in hyperacute xenograft rejection; induction of immunological tolerance to horse IgG as a means to prevent anaphylactic reactions during ALG therapy; development and clinical implementation of the extracorporeal shock wave lithotripsy for extracorporeal destruction of renal and ureteral calculi. The legacy of Brendel continues with the foundation of the Walter-Brendel Kolleg für Transplantationsmedizin (i.e., the German Transplant School for Transplantation Medicine), which has been held annually since 1994.

Upregulated Expression of Janus Kinase Genes in T Cell-Mediated Acute Kidney Allograft Rejection

Background: T-cell-mediated acute kidney transplant rejection (TCMR) is a post-transplantation complication characterized by the infiltration of immune cells into the tissue and sudden dysfunction of the allograft. To develop effective diagnostic and therapeutic methods, it is crucial to understand the molecular mechanisms involved in the initiation and progression of TCMR. Janus kinase (JAK) enzymes, which are involved in proinflammatory cytokine signal transduction, may play a role in TCMR. Given the recent development of JAK inhibitors, the role of JAK molecules should be explored to determine whether they could be potential targets for the treatment of TCMR. Objectives: The study aimed to compare the relative expression of JAK-1, JAK-2, and JAK-3 genes between patients diagnosed with TCMR and stable recipients. Methods: The expression of JAK-1, JAK-2, and JAK-3 genes was evaluated in peripheral blood monocytes of 30 patients with TCMR and 30 stable patients using the RT-PCR method. Results: Janus kinase-1 gene expression in TCMR patients was significantly higher compared to stable patients (P-value = 0.02). However, the relative expression of JAK-2 and JAK-3 genes was comparable between the two groups. Additionally, there was a negative correlation between JAK-1 and JAK-3 gene expression and the estimated glomerular filtration rate in the studied population (P-value = 0.01 and 0.029, respectively). Conclusions: Janus kinase-1 gene expression increased significantly during TCMR of the kidney transplant. Therefore, specific inhibition of this molecule by JAK inhibitor drugs might be considered a therapeutic option for treating TCMR.

P.272: Four-drug immunosuppressive treatment as rescue therapy in kidney transplant recipients with repeated episodes of acute rejection or chronic allograft rejection.

P.272: Four-drug immunosuppressive treatment as rescue therapy in kidney transplant recipients with repeated episodes of acute rejection or chronic allograft rejection.

305.8: Association of donor vascular endothelial growth factor gene polymorphisms with risk of acute kidney allograft rejection.

305.8: Association of donor vascular endothelial growth factor gene polymorphisms with risk of acute kidney allograft rejection.

Capecitabine mitigates cardiac allograft rejection via inhibition of TYMS-Mediated Th1 differentiation in mice

ObjectivesPrevious studies elucidated that capecitabine (CAP) works as an anti-tumor agent with putative immunosuppressive effects. However, the intricate mechanisms underpinning these effects remain to be elucidated. In this study, we aimed to unravel the molecular pathways by which CAP exerts its immunosuppressive effects to reduce allograft rejection. MethodsHearts were transplanted from male BALB/c donors to male C57BL/6 recipients and treated with CAP for seven days. The rejection of these heart transplants was assessed using a range of techniques, including H&E staining, immunohistochemistry, RNA sequencing, LS-MS/MS, and flow cytometry. In vitro, naïve CD4+ T cells were isolated and cultured under Th1 condition medium with varying treatments, flow cytometry, LS-MS/MS were employed to delineate the role of thymidine synthase (TYMS) during Th1 differentiation. ResultsCAP treatment significantly mitigated acute allograft rejection and enhanced graft survival by reducing graft damage, T cell infiltration, and levels of circulating pro-inflammatory cytokines. Additionally, it curtailed CD4+ T cell proliferation and the presence of Th1 cells in the spleen. RNA-seq showed that TYMS, the target of CAP, was robustly increased post-transplantation in splenocytes. In vitro, TYMS and its metabolic product dTMP were differentially expressed in Th0 and Th1, and were required after activation of CD4+ T cell and Th1 differentiation. TYMS-specific inhibitor, raltitrexed, and the metabolite of capecitabine, 5-fluorouracil, could inhibit the proliferation and differentiation of Th1. Finally, the combined use of CAP and the commonly used immunosuppressant rapamycin can induce long-term survival of allograft. ConclusionCAP undergoes metabolism conversion to interfere pyrimidine metabolism, which targets TYMS-mediated differentiation of Th1, thereby playing a significant role in mitigating acute cardiac allograft rejection in murine models.

QuantiFERON CMV Test and CMV Serostatus in Lung Transplant: Stratification Risk for Infection, Chronic and Acute Allograft Rejection.

The QuantiFERON CMV (QCMV) test evaluates specific adaptive immune system activity against CMV by measuring IFN-γ released by activated CD8+ T lymphocytes. We aimed to evaluate the QCMV test as a predictive tool for CMV manifestations and acute or chronic lung allograft rejection (AR and CLAD) in lung transplant (LTx) patients. A total of 73 patients were divided into four groups based on donor and recipient (D/R) serology for CMV and QCMV assay: group A low-risk for CMV infection and disease (D-/R-); group B and C at intermediate-risk (R+), group B with non-reactive QCMV and group C with reactive QCMV; group D at high-risk (D+/R-). Group D patients experienced higher viral replication; no differences were observed among R+ patients of groups B and C. D+/R- patients had a higher number of AR events and group C presented a lower incidence of AR. Prevalence of CLAD at 24 months was higher in group B with a higher risk of CLAD development (OR 6.33). The QCMV test allows us to identify R+ non-reactive QCMV population as the most exposed to onset of CLAD. This population had a higher, although non-significant, susceptibility to AR compared to the R+ population with reactive QCMV.

Adverse Pregnancy Outcomes in Solid Organ Transplant Recipients

Transplant recipients experience high rates of adverse pregnancy outcomes; however, contemporary estimates of the association between solid organ transplantation and adverse pregnancy outcomes are lacking. To evaluate the association between solid organ transplantation and adverse pregnancy outcomes and to quantify the incidence of allograft rejection and allograft loss during pregnancy. PubMed/MEDLINE, EMBASE and Scopus databases were searched from January 1, 2000, to June 20, 2024, and reference lists were manually reviewed. Cohort and case-control studies that reported at least 1 adverse pregnancy outcome in pregnant women with solid organ transplantation vs without solid organ transplant or studies that reported allograft outcomes in pregnant women with solid organ transplantation were included following independent dual review of abstracts and full-text articles. Two investigators abstracted data and independently appraised risk of bias using the Newcastle Ottawa Scale. A random-effects model was used to calculate overall pooled estimates using the DerSimonian-Laird estimator. Reporting followed the Meta-analysis of Observational Studies in Epidemiology (MOOSE) reporting guideline. Primary pregnancy outcomes were preeclampsia, preterm birth (<37 weeks), and low birth weight (<2500 g). Secondary pregnancy outcomes were live birth rate, gestation, very preterm birth (<32 weeks), very low birth weight (<1500 g), and cesarean delivery. Allograft outcomes were allograft loss and rejection during pregnancy. Data from 22 studies and 93 565 343 pregnancies (4786 pregnancies in solid organ transplant recipients) were included; 14 studies reported adverse pregnancy outcomes, and 13 studies provided data for allograft outcomes. Pregnancies in organ transplant recipients were associated with significantly increased risk of preeclampsia (adjusted odds ratio [aOR], 5.83 [95% CI, 3.45-9.87]; I2 = 77.4%), preterm birth (aOR, 6.65 [95% CI, 4.09-12.83]; I2 = 81.8%), and low birth weight (aOR, 6.51 [95% CI, 2.85-14.88]; I2 = 90.6%). The incidence of acute allograft rejection was 2.39% (95% CI, 1.20%-3.96%; I2 = 68.5%), and the incidence of allograft loss during pregnancy was 1.55% (95% CI, 0.05%-4.44%; I2 = 69.2%). In this systematic review and meta-analysis, pregnancies in recipients of a solid organ transplant were associated with a 4 to 6 times increased risk of preeclampsia, preterm birth, and low birth weight during pregnancy. There was a low overall risk of graft rejection or loss during pregnancy.

Comparative outcomes of DSA positive, crossmatch negative living donor kidney transplants versus remaining on the waitlist for an HLA compatible deceased donor

IntroductionThe clinical relevance of preformed donor specific antibodies in the setting of a negative crossmatch (DSA + XM-) remains controversial. In this study we investigate the outcomes of patients with a DSA + XM- living donor (LDi) who proceeded with an HLA-incompatible (HLAi) transplant compared with those who waited for an HLA-compatible deceased donor (DDc). Materials and methodsWe investigated 359 patients on the transplant waiting list who had at least one potential HLAi living donor, from which 203 DSA + XM- pairs were identified and outcomes analysed. ResultsOut of 203 patients, 96 (47.3%) received a LD transplant: 52/96 (54.2%) a LDi, and 44/96 (45.8%) an alternative compatible LD. In addition, 107 patients out of 203(52.7%) waited for a DDc, of which 47(43.9%) were subsequently transplanted. Our adjusted analysis showed that the LDi transplantation did not offer a superior patient survival over waiting for a DDc transplant. For those transplanted, there was no difference in patient (p = 0.065) or death censored allograft survival (p = 0.37) between DDc and LDi recipients. However, there was a higher incidence of acute allograft rejection (p = 0.043) and antibody-mediated rejection (p = 0.005) in the LDi group. Having a high pre-transplant calculated reaction frequency and preformed DSA to both class I and class II antigens were associated with inferior outcomes in the LDi transplants. ConclusionsGiven the lack of difference in allograft survival between LDi and DDc transplants, in the absence of an alternative compatible living donor, proceeding with a LDi should be supported despite a higher rejection risk, providing individual risk assessment and shared decision making is undertaken.

Impact of Serum IL 10 on Early Prediction of Allograft Rejection in Liver Transplantation

Abstract Background Tissue transplantation is the preferred treatment for end organ failure such as heart, lung, kidney and liver. Unless the donor and recipient of a transplant are genetically identical, the donated tissue is viewed by the immune system of the recipient as non-self. multiple cytokines are involved in this process, however little is known about their predictive role in rejection. IL10 which exhibit anti-inflammatory activity could be used as early predictor of acute rejection. Objective The aim of the current study is to evaluate the possible association between serum IL10 level in liver transplant patients and acute allograft rejection. Patients and Method: This study was conducted on 45 subjects. Patients will be followed up for 2months and they will be further divided into two groups: Those who developed early acute rejection and those who did not develop rejection (controls) Result The study included 38 patients did not develop rejection and 7 patients developed rejection. We found unchanged during rejection of the LT of the levels of IL-10 Conclusion Several studymust be conducted on cytokines on large sample size to prove early prediction of acute rejection

Lymphotoxin β receptor and tertiary lymphoid organs shape acute and chronic allograft rejection.

Solid organ transplantation remains the life-saving treatment for end-stage organ failure, but chronic rejection remains a major obstacle to long-term allograft outcomes and has not improved substantially. Tertiary lymphoid organs (TLOs) are ectopic lymphoid structures that form under conditions of chronic inflammation, and evidence from human transplantation suggests that TLOs regularly form in allografts undergoing chronic rejection. In this study, we utilized a mouse renal transplantation model and manipulation of the lymphotoxin αβ/lymphotoxin β receptor (LTαβ/LTβR) pathway, which is essential for TLO formation, to define the role of TLOs in transplantation. We showed that intragraft TLOs are sufficient to activate the alloimmune response and mediate graft rejection in a model where the only lymphoid organs are TLOs in the allograft. When transplanted to recipients with a normal set of secondary lymphoid organs, the presence of graft TLOs or LTα overexpression accelerated rejection. If the LTβR pathway was disrupted in the donor graft, TLO formation was abrogated, and graft survival was prolonged. Intravital microscopy of renal TLOs demonstrated that local T and B cell activation in TLOs is similar to that observed in secondary lymphoid organs. In summary, we demonstrated that immune activation in TLOs contributes to local immune responses, leading to earlier allograft failure. TLOs and the LTαβ/LTβR pathway are therefore prime targets to limit local immune responses and prevent allograft rejection. These findings are applicable to other diseases, such as autoimmune diseases or tumors, where either limiting or boosting local immune responses is beneficial and improves disease outcomes.

C-reactive protein orchestrates acute allograft rejection in vascularized composite allotransplantation via selective activation of monocyte subsets

IntroductionDespite advancements in transplant immunology and vascularized composite allotransplantation (VCA), the longevity of allografts remains hindered by the challenge of allograft rejection. The acute-phase response, an immune-inflammatory reaction to ischemia/reperfusion that occurs directly after allogeneic transplantation, serves as a catalyst for graft rejection. This immune response is orchestrated by acute-phase reactants through intricate crosstalk with the mononuclear phagocyte system. ObjectiveC-reactive protein (CRP), a well-known marker of inflammation, possesses pro-inflammatory properties and exacerbates ischemia/reperfusion injury. Thus, we investigated how CRP impacts acute allograft rejection. MethodsPrompted by clinical observations in facial VCAs, we employed a complex hindlimb transplantation model in rats to investigate the direct impact of CRP on transplant rejection. ResultsOur findings demonstrate that CRP expedites allograft rejection and diminishes allograft survival by selectively activating non-classical monocytes. Therapeutic stabilization of CRP abrogates this activating effect on monocytes, thereby attenuating acute allograft rejection. Intravital imagining of graft-infiltrating, recipient-derived monocytes during the early phase of acute rejection corroborated their differential regulation by CRP and their pivotal role in driving the initial stages of graft rejection. ConclusionThe differential activation of recipient-derived monocytes by CRP exacerbates the innate immune response and accelerates clinical allograft rejection. Thus, therapeutic targeting of CRP represents a novel and promising strategy for preventing acute allograft rejection and potentially mitigating chronic allograft rejection.