American ginseng with different processing methods ameliorate immunosuppression induced by cyclophosphamide in mice via the MAPK signaling pathways.

This study aimed to clarify the effects of two processed forms of American ginseng (Panax quinquefolius L.) on immunosuppression caused by cyclophosphamide (CTX) in mice. In the CTX-induced immunosuppressive model, mice were given either steamed American ginseng (American ginseng red, AGR) or raw American ginseng (American ginseng soft branch, AGS) by intragastric administration. Serum and spleen tissues were collected, and the pathological changes in mice spleens were observed by conventional HE staining. The expression levels of cytokines were detected by ELISA, and the apoptosis of splenic cells was determined by western blotting. The results showed that AGR and AGS could relieve CTX-induced immunosuppression through the enhanced immune organ index, improved cell-mediated immune response, increased serum levels of cytokines (TNF-α, IFN-γ, and IL-2) and immunoglobulins (IgG, IgA, and IgM), as well as macrophage activities including carbon clearance and phagocytic index. AGR and AGS downregulated the expression of BAX and elevated the expression of Bcl-2, p-P38, p-JNK, and p-ERK in the spleens of CTX-injected animals. Compared to AGS, AGR significantly improved the number of CD4+CD8-T lymphocytes, the spleen index, and serum levels of IgA, IgG, TNF-α, and IFN-γ. The expression of the ERK/MAPK pathway was markedly increased. These findings support the hypothesis that AGR and AGS are effective immunomodulatory agents capable of preventing immune system hypofunction. Future research may investigate the exact mechanism to rule out any unforeseen effects of AGR and AGS.

Specific immune response to mRNA vaccines against COVID-19 in patients receiving allogeneic stem cell transplantation for myeloid malignancy was altered by immunosuppressive therapy.

BACKGROUND: Allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients are at high risk of complications associated with COVID-19 infection due to dysfunction of their immune system. Vaccination can protect from the adverse consequences of COVID-19. However, studies on the efficacy of COVID-19 vaccines in HSCT recipients with insufficient post-HSCT immune reconstitution are still scarce. In our study, we determined how immunosuppressive medication and the reconstitution of the cellular immune system influenced T cell responses specific for the surface glycoprotein of SARS-CoV-2 virus (S antigen) after two doses of mRNA vaccine against COVID-19 in patients with myeloid malignancies treated with HSCT. METHODS: Vaccination outcomes were followed in 18 (allo-HSCT) recipients and 8 healthy volunteers. The IgG antibodies against SARS-CoV-2 spike (S) and nucleocapsid (NCP) protein were determined in ELISA and S-specific T cells were detected using a sensitive ELISPOT-IFNγ based on in vitro expansion and restimulation of T cells in pre- and post-vaccination blood samples. Multiparametric flow cytometry analysis of peripheral blood leukocyte differentiation markers was employed for determination of reconstitution of the main subpopulations of T cells and NK cells at month 6 after HSCT. RESULTS: S- specific IgG antibody response detected in 72% of the patients was lower than in healthy vaccinees (100%). Vaccine-induced T-cell responses to S1 or S2 antigen were significantly reduced in HSCT recipients, which were treated with corticosteroids in dose 5 mg of prednisone- equivalents or higher during the vaccination period or in preceeding 100 days in comparison with recipients un-affected with corticosteroids. A significant positive correlation was found between the level of anti-SARS-Cov-2 spike protein IgG antibodies and the number of functional S antigen-specific T cells. Further analysis also showed that the specific response to vaccination was significantly influenced by the interval between administration of vaccine and transplantation. Vaccination outcomes were not related to age, sex, type of mRNA vaccine used, basic diagnosis, HLA match between HSC donor and recipient, and blood counts of lymphocytes, neutrophils, and monocytes at the time of vaccination. Multiparametric flow cytometry analysis of peripheral blood leukocyte differentiation markers showed that good humoral and cellular S-specific immune responses induced by vaccination were associated with well-reconstituted CD4+ T cells, mainly CD4+ effector memory subpopulation at six months after HSCT. CONCLUSIONS: The results showed that both humoral and cellular adaptive immune responses of HSCT recipients to the SARS-CoV-2 vaccine were significantly suppressed by corticosteroid therapy. Specific response to the vaccine was significantly affected by the length of the interval between HSCT and vaccination. Vaccination as early as 5 months after HSCT can lead to a good response. Immune response to the vaccine is not related to age, gender, HLA match between HSC donor and recipient, or type of myeloid malignancy. Vaccine efficacy was dependent on well-reconstituted CD4+ T cells, at six months after HSCT.

COVID-19 in patients with glomerular disease.

PURPOSE OF REVIEW: Managing patients with glomerular disease during the COVID-19 pandemic has been challenging, as the infection risk associated with immunosuppression must be balanced against the need to control severe glomerular disease that can lead to kidney failure. This review provides an overview of COVID-19 and the effectiveness of SARS-CoV-2 vaccination in patients with glomerular disease. RECENT FINDINGS: Registry data, although biased towards outcomes of hospitalized patients, suggest that the mortality from COVID-19 is higher in patients with glomerular disease than in the general population. Glucocorticoid use prior to SARS-CoV-2 infection is associated with adverse outcomes from COVID-19. Rituximab significantly attenuates serological responses to both natural infection and vaccination against SARS-CoV-2, although it is not clear whether this leads to adverse outcomes. Case reports of disease flares occurring after vaccination have been reported, but causality in any of these cases has yet to be proven and the absolute risk remains very small. SUMMARY: Patients with glomerular disease represent an at-risk group for severe COVID-19 disease and vaccination is key to reducing this risk. As immunosuppressed patients demonstrate an attenuated response to vaccination, the efficacy of a third primary dose followed by a subsequent booster is being investigated.

Immunosuppression as a Hub for SARS-CoV-2 Mutational Drift.

The clinical course of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is largely determined by host factors, with a wide range of outcomes. Despite an extensive vaccination campaign and high rates of infection worldwide, the pandemic persists, adapting to overcome antiviral immunity acquired through prior exposure. The source of many such major adaptations is variants of concern (VOCs), novel SARS-CoV-2 variants produced by extraordinary evolutionary leaps whose origins remain mostly unknown. In this study, we tested the influence of factors on the evolutionary course of SARS-CoV-2. Electronic health records of individuals infected with SARS-CoV-2 were paired to viral whole-genome sequences to assess the effects of host clinical parameters and immunity on the intra-host evolution of SARS-CoV-2. We found slight, albeit significant, differences in SARS-CoV-2 intra-host diversity, which depended on host parameters such as vaccination status and smoking. Only one viral genome had significant alterations as a result of host parameters; it was found in an immunocompromised, chronically infected woman in her 70s. We highlight the unusual viral genome obtained from this woman, which had an accelerated mutational rate and an excess of rare mutations, including near-complete truncating of the accessory protein ORF3a. Our findings suggest that the evolutionary capacity of SARS-CoV-2 during acute infection is limited and mostly unaffected by host characteristics. Significant viral evolution is seemingly exclusive to a small subset of COVID-19 cases, which typically prolong infections in immunocompromised patients. In these rare cases, SARS-CoV-2 genomes accumulate many impactful and potentially adaptive mutations; however, the transmissibility of such viruses remains unclear.

Managing Immunosuppression in Vasculitis Patients in Times of Coronavirus Disease 2019.

The coronavirus disease 2019 (COVID-19) pandemic has led to the emergence of multiple challenges in the care of patients with systemic rheumatic diseases. Patients with vasculitis represent a group of particular concern due to existing risk factors which include a higher burden of comorbidities and specific immunosuppressive therapies used for treatment. Vaccination and the use of other risk mitigation strategies are crucial for the care of these patients. This review provides an overview of existing evidence to contribute to the understanding and specific requirements of the treatment and management of patients with vasculitis during the time of COVID-19.

Immunosuppressive treatment for autoimmune blistering diseases does not impair production of neutralizing antibodies after "booster" dose of COVID-19 vaccine.

Since vaccines against COVID-19 are available, it has been debated if immunosuppressed patients with autoimmune blistering diseases (AIBDs) should be advised to interrupt the immunosuppressive therapy before receiving the vaccine, with consequent risk to experience a flare of disease. In the present study, we measured the neutralizing antibodies production after anti-SARS-CoV-2 vaccination in patients with AIBDs on immunosuppressive treatment, compared to healthy controls. Our results give strength to the hypothesis that these patients do not need to discontinue their therapy to produce effective levels of neutralizing antibodies, in other words to achieve successful protection.

Management of immunosuppressants in the era of coronavirus disease-2019.

PURPOSE OF REVIEW: Patients on chronic immunosuppressive treatments at baseline are at increased risk of opportunistic infections. These patients are at especially increased risk of morbidity and mortality during the coronavirus-19 (COVID-19) pandemic. This review will focus on patients with diseases in which immunosuppression is a vital part of the treatment regimen, including those with solid organ transplants, rheumatologic disorders, sarcoidosis, and inflammatory bowel disease (IBD). We will summarize the current knowledge of immunosuppression in these diseases and the risk of contracting COVID-19. Furthermore, we will discuss if immunosuppression increases severity of COVID-19 presentation. RECENT FINDINGS: Since the start of the COVID-19 pandemic, a large number patients receiving chronic immunosuppression have been infected with SARS-CoV-2. Moreover, our understanding of the immunology of SARS-CoV-2 is advancing at a rapid pace. Currently, a number of clinical trials are underway to investigate the role of immunosuppressive treatments in the management of this disease. SUMMARY: Currently, there is no conclusive evidence to suggest that solid organ transplant recipients on chronic immunosuppression are at increased risk of contracting COVID-19. Solid organ transplant recipients may be at increased risk for worse COVID-19 outcomes but the data are not consistent. There is evidence to suggest that patients with rheumatologic disorders or IBDs are not at increased risk of contracting COVID-19 and do not necessarily experience worse clinical outcomes. Patients with sarcoidosis are not necessarily at increased risk of COVID-19, although there is limited data available to determine if immunosuppression worsens outcomes in this population.

COVID-19 in kidney transplant recipients.

There is minimal information on coronavirus disease 2019 (COVID-19) in immunocompromised individuals. We have studied 10 patients treated at 12 adult care hospitals. Ten kidney transplant recipients tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by polymerase chain reaction, and 9 were admitted. The median age was 57 (interquartile range [IQR] 47-67), 60% were male, 40% Caucasian, and 30% Black/African American. Median time from transplant to COVID-19 testing was 2822 days (IQR 1272-4592). The most common symptom was fever, followed by cough, myalgia, chills, and fatigue. The most common chest X-ray and computed tomography abnormality was multifocal patchy opacities. Three patients had no abnormal findings. Leukopenia was seen in 20% of patients, and allograft function was stable in 50% of patients. Nine patients were on tacrolimus and a mycophenolic antimetabolite, and 70% were on prednisone. Hospitalized patients had their antimetabolite agent stopped. All hospitalized patients received hydroxychloroquine and azithromycin. Three patients died (30%), and 5 (50%) developed acute kidney injury. Kidney transplant recipients infected with COVID-19 should be monitored closely in the setting of lowered immunosuppression. Most individuals required hospitalization and presenting symptoms were similar to those of nontransplant individuals.

A multicentre, patient- and assessor-blinded, non-inferiority, randomised and controlled phase II trial to compare standard and torque teno virus-guided immunosuppression in kidney transplant recipients in the first year after transplantation: TTVguideIT.

BACKGROUND: Immunosuppression after kidney transplantation is mainly guided via plasma tacrolimus trough level, which cannot sufficiently predict allograft rejection and infection. The plasma load of the non-pathogenic and highly prevalent torque teno virus (TTV) is associated with the immunosuppression of its host. Non-interventional studies suggest the use of TTV load to predict allograft rejection and infection. The primary objective of the current trial is to demonstrate the safety, tolerability and preliminary efficacy of TTV-guided immunosuppression. METHODS: For this purpose, a randomised, controlled, interventional, two-arm, non-inferiority, patient- and assessor-blinded, investigator-driven phase II trial was designed. A total of 260 stable, low-immunological-risk adult recipients of a kidney graft with tacrolimus-based immunosuppression and TTV infection after month 3 post-transplantation will be recruited in 13 academic centres in six European countries. Subjects will be randomised in a 1:1 ratio (allocation concealment) to receive tacrolimus either guided by TTV load or according to the local centre standard for 9 months. The primary composite endpoint includes the occurrence of infections, biopsy-proven allograft rejection, graft loss, or death. The main secondary endpoints include estimated glomerular filtration rate, graft rejection detected by protocol biopsy at month 12 post-transplantation (including molecular microscopy), development of de novo donor-specific antibodies, health-related quality of life, and drug adherence. In parallel, a comprehensive biobank will be established including plasma, serum, urine and whole blood. The date of the first enrolment was August 2022 and the planned end is April 2025. DISCUSSION: The assessment of individual kidney transplant recipient immune function might enable clinicians to personalise immunosuppression, thereby reducing infection and rejection. Moreover, the trial might act as a proof of principle for TTV-guided immunosuppression and thus pave the way for broader clinical applications, including as guidance for immune modulators or disease-modifying agents. TRIAL REGISTRATION: EU CT-Number: 2022-500024-30-00.

Mucormycosis, past and present: a comprehensive review.

Mucormycosis is an emerging opportunistic angioinvasive fungal infection. Predisposing factors such as diabetes, neutropenia, long-term corticosteroid therapy, solid organ transplantation and immunosuppression contribute to its occurrence. This disease was not of significant concern prior to the COVID-19 pandemic, but gained prominence due to infections in COVID-19 patients. Mucormycosis needs special attention and coordinated efforts of the scientific community and medical professionals to reduce morbidity and mortality. Here we present an overview of the epidemiology and prevalence of mucormycosis in the pre- and post-COVID-19 eras, the factors that contributed to the abrupt increase in COVID-19-associated mucormycosis (CAM), the actions taken by the regulatory agencies (including Code Mucor and CAM registry), the existing diagnostic tools and CAM management strategies.

The devastating effects of the COVID-19 pandemic have been further enhanced by various secondary illnesses, particularly opportunistic fungal infections such as mucormycosis. Mucormycosis or 'black fungus' primarily affects people with weakened immunity, those with medical conditions such as diabetes or cancer and those who use medications that reduce the body's capacity to resist infections and disease. The infection starts in the sinuses or the lungs after breathing in spores of the black fungus from the air. In just 2 months between 5 May and 12 July 2021, this uncommon but fatal fungal illness was responsible for 41,512 cases and 3554 fatalities in India alone. The government of India declared a mucormycosis epidemic in May 2021. The majority of such cases occurred during active SARS-CoV-2 outbreaks in India in 2021. Black fungus took over while the host defenses were compromised and the globe was preoccupied tackling the COVID-19 pandemic. Steroids prescribed in amounts and time spans that far exceeded WHO recommendations to manage severe COVID-19 cases, potentially weakened patients' immune systems, and raised blood sugar levels making them vulnerable to fungal invasion. Early diagnosis and treatment are the keys to a patient's survival. Simple means such as maintaining hygienic conditions, avoiding contact with an infected person, judiciously using steroid medications and antibiotics and properly managing high blood sugar can help protect an individual from black-fungus infection.

SARS-CoV-2 infection in adult liver transplantation recipients: a systematic review of risk factors for mortality and immunosuppression role.

OBJECTIVE: Data on mortality, immunosuppression, and vaccination role regarding liver transplant (LT) recipients affected by COVID-19 are still under debate. This study aims to identify risk factors for mortality and the role of immunosuppression in COVID-19 LT recipients. MATERIALS AND METHODS: A systematic review of SARS-CoV-2 infection in LT recipients was performed. The primary outcomes were risk factors for mortality, the role of immunosuppression and vaccination. A meta-analysis was not performed as there was a different metric of the same outcome (mortality) and a lack of a control group in most studies. RESULTS: Overall, 1,343 LT recipients of 1,810 SOT were included, and data on mortality were available for 1,110 liver transplant recipients with SARS-CoV-2 infection. Mortality ranged between 0-37%. Risk factors of mortality were age >60 years, Mofetil (MMF) use, extra-hepatic solid tumour, Charlson Comorbidity Index, male sex, dyspnoea at diagnosis, higher baseline serum creatinine, congestive heart failure, chronic lung disease, chronic kidney disease, diabetes, BMI >30. Only 51% of 233 LT patients presented a positive response after vaccination, and older age (>65y) and MMF use were associated with lower antibodies. Tacrolimus (TAC) was identified as a protective factor for mortality. CONCLUSIONS: Liver transplant patients present additional risk factors of mortality related to immunosuppression. Immunosuppression role in the progression to severe infection and mortality may correlate with different drugs. Moreover, fully vaccinated patients have a lower risk of developing severe COVID-19. The present research suggests safely using TAC and reducing MMF use during the COVID-19 pandemic.

Reduced neutralizing antibody response to SARS-CoV-2 vaccine booster dose in people living with HIV with severe immunosuppression.

The aim of this study was to assess the immunogenicity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines among people living with HIV (PLWH) with severe immunosuppression, after a booster dose. The design was a case-control study nested in a prospective cohort of PLWH. All patients with CD4 cell count <200 cells/mm3 who had received additional dose of messenger RNA (mRNA) COVID-19 vaccine, after a standard immunization scheme were included. Control group: patients age- and sex-matched, with CD4 ≥ 200 cells/mm3 , in the ratio of 2:1. Antibody response to a booster dose (anti-S levels 33.8 ≥ BAU/mL) and neutralizing activity against SARS-CoV-2 B.1, B.1.617.2, and Omicron BA.1, BA.2, and BA.5 strains were assessed after the booster shot. Fifty-four PLWH were included, 18 with CD4 counts < 200 cells/mm3 . Fifty-one (94%) showed response to a booster dose. Response was less frequent in PLWH with CD4 < 200 cells/mm3 than in those with CD4 counts ≥ 200 cells/mm3 (15 [83%] vs. 36 [100%], p = 0.033). In the multivariate analysis, CD4 counts ≥ 200 cells/mm3 [incidence rate ratio (IRR) = 18.1 (95% confidence interval [CI]: 16.8-19.5), p < 0.001] was associated with a higher probability of showing antibody response. Neutralization activity against SARS-CoV-2 B.1, B.1.617, BA.1, and BA.2 strains was significantly inferior among individuals with CD4 counts < 200 cells/mm3 . In conclusion, among PLWH with CD4 counts < 200 cells/mm3 , the immune response elicited by mRNA additional vaccine dose is reduced.

Clinical Characteristics of Strongyloidiasis during the COVID-19 Pandemic: Systematic Scoping Review.

The clinical impact of Strongyloides stercoralis hyperinfection secondary to immunosuppressive therapy for coronavirus disease 2019 (COVID-19) has been an emerging topic of interest, although characteristics of Strongyloides infection in COVID-19 patients are not yet well characterized. This study summarizes the existing evidence of Strongyloides infection in COVID-19 patients and recommends future areas of research. According to the PRISMA Extension for Scoping Reviews, we performed a search on MEDLINE and EMBASE for articles with keywords including "Strongyloides," "Strongyloidiasis," and "COVID-19" from the inception of these databases to June 5, 2022. A total of 104 articles were found. After excluding duplication and thorough reviews, 11 articles, including two observational studies, one conference abstract, and nine case reports or series, were included. Two observational studies focused on revealing the prevalence of Strongyloides screening in COVID-19 patients and clinical follow-up. Among the included cases, patients were mostly from low- or middle-income countries and suffered from severe or critical COVID-19. Strongyloides hyperinfection and disseminated infection were reported in 60% and 20%, respectively. Interestingly, 40% did not have eosinophilia, a hallmark of parasitic infection, potentially leading to delay in diagnosis of strongyloidiasis. This systematic review summarizes the clinical characteristics of strongyloidiasis in COVID-19 infection. Although further studies to identify risks and precipitants associated with the onset of strongyloidiasis are crucial, increased awareness of the critical condition is warranted.

A Novel Case Report of Severe Aplastic Anemia with COVID Infection.

Aplastic anemia is a rare disease of the hematopoietic system. Although some viral agents have been implicated, the association between COVID-19 and aplastic anemia is unclear. In this way, several cases of aplastic anemia have been reported following infection with COVID-19. Importantly, we reported a 16-year-old girl with severe aplastic anemia with no history of disease following an Omicron infection who did not respond well to treatment despite supportive treatment and immunosuppression.

Pediatric Systemic Lupus Erythematous in COVID-19 Era.

Pediatric systemic lupus erythematosus is a chronic autoimmune disorder with a highly variable course and prognosis. It results in functional abnormalities in the immune system due to intrinsic factors and the use of immunosuppressive therapies associated with underlying comorbidities seem to increase the risk of severe COVID-19 and poor outcomes of the disease in pediatric systemic lupus erythematosus (SLE) patients. The aim of this review is to obtain a better understanding of the existing link between this new viral infection and pediatric lupus. We have analyzed the characteristics of newly diagnosed cases of pediatric SLE following COVID-19 which have been reported in the literature and which describe the impact that COVID-19 has on patients already suffering with pediatric SLE.

Trilogy of COVID-19: Infection, Vaccination, and Immunosuppression.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative respiratory pathogen responsible for coronavirus disease 2019 (COVID-19). In 2020, the power of open science was visible to all, as novel vaccinology led to rapid establishment of vaccine clinical trials, and subsequent authorization of SARS-CoV-2 at an unprecedented pace. This evoked rapid deployment of SARS-CoV-2 vaccines and booster doses to keep with the ever-changing landscape of SARS-CoV-2. In this review, we provide an overview of vaccine efficacy studies, which have been well characterized in healthy individuals. Nevertheless, vaccine efficacy within the immunosuppressed is less well characterized, as these individuals were omitted from initial efficacy studies. Consequently, vaccine-induced responses in this group are relatively unknown. Currently, limited evidence investigating vaccine efficacy within the immunosuppressed is available. Here, we provide an overview of SARS-CoV-2 infection and associated pathogenesis. Furthermore, we undertake a critical analysis of observed vaccine responses from clinical studies, conducted in healthy and immunosuppressed populations. Whilst vaccine deployment has curbed mortality, there are significant challenges that lie ahead. This includes correlating vaccine responses with protective immunity and ensuring that global vaccine equity is met.

Virus-Associated Nephropathies: A Narrative Review.

While most viral infections cause mild symptoms and a spontaneous favorable resolution, some can lead to severe or protracted manifestations, specifically in immunocompromised hosts. Kidney injuries related to viral infections may have multiple causes related to the infection severity, drug toxicity or direct or indirect viral-associated nephropathy. We review here the described virus-associated nephropathies in order to guide diagnosis strategies and treatments in cases of acute kidney injury (AKI) occurring concomitantly with a viral infection. The occurrence of virus-associated nephropathy depends on multiple factors: the local epidemiology of the virus, its ability to infect renal cells and the patient's underlying immune response, which varies with the state of immunosuppression. Clear comprehension of pathophysiological mechanisms associated with a summary of described direct and indirect injuries should help physicians to diagnose and treat viral associated nephropathies.

Association between PIRCHE-II scores and de novo allosensitization after reduction of immunosuppression during SARS-CoV-2 infection in kidney transplant recipients.

BACKGROUND: Before the availability of mRNA vaccines, many transplant centers chose to significantly reduce maintenance immunosuppression in kidney transplant recipients (KTRs) with SARS-CoV-2 infection. The extent to which this increases the risk of allosensitization is unclear. METHODS: In this observational cohort study, we analyzed 47 KTRs from March 2020 to February 2021 who underwent substantial reduction of maintenance immunosuppression during SARS-CoV-2 infection. KTRs were followed at 6 and 18 months concerning the development of de novo donor-specific anti-HLA (human leukocyte antigen) antibodies (DSA). The HLA-derived epitope mismatches were calculated using the predicted indirectly recognizable HLA-epitopes (PIRCHE-II) algorithm. RESULTS: In total, 14 of 47 KTRs (30%) developed de novo HLA antibodies after the reduction of maintenance immunosuppression. KTRs with higher total PIRCHE-II scores and higher PIRCHE-II scores for the HLA-DR locus were more likely to develop de novo HLA antibodies (p = .023, p = .009). Furthermore, 4 of the 47 KTRs (9%) developed de novo DSA after reduction of maintenance immunosuppression, which were exclusively directed against HLA-class II antigens and also showed higher PIRCHE-II scores for HLA-class II. The cumulative mean fluorescence intensity of 40 KTRs with preexisting anti-HLA antibodies and 13 KTRs with preexisting DSA at the time of SARS-CoV-2 infection remained stable after the reduction of maintenance immunosuppression (p = .141; p = .529). CONCLUSIONS: Our data show that the HLA-derived epitope mismatch load between donor and recipient influences the risk of de novo DSA development when immunosuppression is temporarily reduced. Our data further suggest that reduction in immunosuppression should be made more cautiously in KTRs with high PIRCHE-II scores for HLA-class II antigens.