Donor-specific HLA Antibodies Research Articles

Rejection and graft outcomes in kidney transplant recipients with and without angiotensin II receptor type 1 antibodies

AimAngiotensin II type 1 receptor antibody (AT1R Ab) is a non-Human Leucocyte Antigen (HLA) antibody that is maybe associated with early severe kidney transplant rejection and worse graft outcomes. This study aimed to assess the association between AT1R Ab and kidney transplant rejection and graft outcomes. MethodsWe performed a retrospective analysis of all adult kidney transplant recipients in an Australian centre who had an AT1R Ab test between 1 January 2015 to 30 June 2020. AT1R Ab positive patients were compared to AT1R Ab negative patients. Primary outcomes were rejection risk, type and histopathological severity scores. Secondary outcomes were 8-week graft function and graft loss. ResultsOf 965 kidney transplants that were performed during the study period, 73 patients had AT1R Ab tested; 16 (22%) were positive and 57(78%) were negative. Positive patients were on average younger and had higher level of donor-specific HLA antibodies. Rejection occurred in 13 (81%) positive patients and 41 (72%) negative patients (P = 0.45). No significant differences in rejection type or severity were found. HLA mismatch and peak panel reactive antibody ≥80%, but not AT1R Ab, independently predicted rejection. Average (132 vs. 177 mmol/L, P = 0.302) and graft loss were not significantly different between groups. ConclusionThe study found no evidence that AT1R Ab is associated with rejection type, severity or worse graft function. Future studies should assess its relationship with graft outcomes to help complement immunological risk assessment and potentially provide therapeutic options to alter outcomes.

Has the Time Come for Widespread MHC Class I MICA Genotyping in Solid Organ Transplantation?

Has the Time Come for Widespread MHC Class I MICA Genotyping in Solid Organ Transplantation?

Effect of preexisting human leukocyte antigen donor-specific antibodies especially human leukocyte antigen-DQ on kidney transplant outcome

Effect of preexisting human leukocyte antigen donor-specific antibodies especially human leukocyte antigen-DQ on kidney transplant outcome

Haploidentical Hematopoietic Cell Transplantation of Ex Vivo Tcrαβ-Depleted Grafts with CD45RA-Depleted Memory T Cell Add-Back Reduces Chronic Graft-Versus-Host Disease and Results in Favourable Gvhd-Relapse Free Survival: 5-Year Follow-up of 107 Patients Treated in a Multicenter Study in Singapore

Background: Haploidentical hematopoietic cell transplantation (HCT) provides an alternative option for patients without HLA-matched donors. Graft-versus-host disease (GVHD), engraftment failure, and infectious complications are main causes of non-relapse mortality (NRM). We hypothesized that selective depletion of TCRαβ+ and CD45RA+ naïve T cells will permit hematopoietic engraftment while effectively reducing GVHD and providing donor immune reconstitution through adoptive transfer of donor's mature NK cells, γδ T cells and CD45RO+ memory T cells. Methods: Mobilized PBSC products were divided into two fractions in 8-9 : 1-2 ratio and depleted using CliniMACS device after labelling with TCRαβ and CD45RA reagents (Miltenyi Biotec, Bergish-Gladbach, Germany) respectively. All except 13 patients received the standard conditioning regimen of fludarabine 160mg/m2 divided daily over 4 days, thiotepa 10mg/kg divided twice daily for 1 day, and melphalan 70 - 140 mg/m2 for 1 day, in combination with either total lymphoid irradiation 6 Gy (n=58) or 7.5 Gy (n=12) over 3 equal fractions, total body irradiation of 2 Gy (n=24), or thymoglobuline (n=2). Short term GVHD prophylaxis was given for 30 days to 1 patient using MMF, 95 using tacrolimus, and 2 using sirolimus. Results: Between January 2017 and July 2022, we transplanted 107 patients, including 100 adults (median age, 52 years; range 19- 70) and 7 children (median age, 13 years, range 7 - 17), with high risk AML (n=60), ALL (n=22), MDS (n=10), plasma cell neoplasm (n=3), mast cell leukemia (n=1), acute undifferentiated leukemia (n=1), CMMoL (n=2), CML (n=2), MPN (n=1) and lymphoma (n=5). Patients were infused with TCRαβ and CD45RA depleted grafts containing a median of 6.18 x 106 (range 2.13 - 20.78) CD34+ cells/kg, 0.00 x 104 (range 0 - 0.97) CD45RA+CD3+ cells/kg, and 1.21 x 106 (range 0.15 - 11.67) CD45RO+CD3+ cells/kg. TCRαβ depleted graft fraction contained a median of 0.37 x 104 (range 0 - 11.30) TCRαβ+ cells/kg, and 7.72 x 106 (range 0.62 - 42.00) TCRγδ+ cells/kg. Only 1 patient experienced primary graft failure with no secondary graft failures. All others had engraftment of ANC > 500 cells/µL at median of 12 days (range 8 - 25) and PLT > 20,000 cells/µL at median of 11 days (range 7 - 17). 10 patients with high donor-specific HLA antibodies (DSA) titres engrafted successfully after desensitisation with plasma exchange, rituximab, immunoglobulin, and irradiated donor buffy coat infusion (n=1). 38 patients (35%) developed acute GVHD of grade II - IV, with a cumulative incidence (CI) of grade II-IV and grade III-IV of 34%, and 12% respectively, at 180 days. Chronic GVHD was seen in only 4 patients at a 2-year CI of 5 % . 1-year CI of non-relapse mortality (NRM) and relapse were 18.4 % and 17.2%, respectively. 4 of the 22 NRM were attributed to aGVHD. Viral reactivation included CMV (n=39), HHV-6 (n=28), EBV (n=19), and adenovirus (n=8). 11 patients (11%) out of the 15 infection-related death (15%) occurred within 180 days. At a median follow up of 23 months (range 0.3- 67.1) in surviving patients, 2-year overall (OS), event-free (EFS), and GVHD-free/relapse-free (GRFS) survival were 69.9 %, 58.7 %, and 57.3 %, respectively (Figure 1). In multivariate analysis, HCT-comorbidity index (HCT-CI) has shown significant impact on OS (p=0.008), EFS (p=0.03), and NRM (p=0.002). Disease risk index (DRI) also showed significant impact on OS (p=0.042), EFS (p=0.02) and relapse (p=0.04). In contrast, NRM was only influenced by HCT-CI (p=0.002). In the subset analysis of 63 patients (adults, n= 58; children, n=5) with favorable HCT-CI score of 0/1 and low/intermediate risk DRI, the 2-year OS, EFS, and GRFS were 75.0 %, 68.6%, and 68.0 %, respectively (Figure 2). Conclusions: Our preliminary results suggest that RIC haplo-HCT with TCRαβ and CD45RA+ depleted grafts allow successful allograft in patients with high-risk haematological malignancies lacking suitable matched donors, including patients with high levels of DSA. Acute GVHD was generally abortive, leading to low incidence of chronic GVHD and favorable GRFS. Best outcomes are seen in patients with favourable HCT-CI and low/intermediate risk DRI. Further efforts are needed to reduce the risk of infection-related death in patients with high risk HCT-CI, and relapse risk in patients with high risk DRI, through optimization of conditioning regimen intensity, anti-microbial prophylaxis or prophylactic infusion of memory-cell DLI. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Both donor specific and non-donor specific HLA antibodies reduced in recipients post simultaneous liver/kidney transplant

It has been suggested that the liver allograft can protect the kidney allograft from antibody mediated rejection in simultaneous liver/kidney transplant (SLK) recipients by reducing preexisting donor specific antibodies (DSA) via adsorption of DSA by the liver allograft. Recently, the SLK allocation system was altered to provide a kidney safety net to those who do not recover native kidney function after liver transplant. However, the kidney transplant under the safety net creates a theoretical challenge for sensitized patients as the liver graft may not be able to adsorb human leukocyte antigen (HLA) antibodies against the kidney under the safety net because the liver and kidney grafts are from different donors and may carry different HLA antigens. This prompts us to examine levels of non-donor specific HLA antibodies in SLK recipients in our hospital. We found that levels of both DSA and non-DSA decreased post SLK transplant. The presence of preexisting DSA was also not associated with kidney graft survival and antibody mediated rejection in SLK recipients. Our results indicate that the liver transplant can reduce non-DSA, which may increase the pool of compatible kidneys offered under the safety net program for sensitized patients.

Immunology of simultaneous liver and kidney transplants with identification and prevention of rejection.

Simultaneous liver and kidney (SLK) transplantation is considered the best treatment modality among selected patients with both chronic kidney disease (CKD) and end-stage liver disease (ESLD). Since the first SLK transplant in 1983, the number of SLK transplants has increased worldwide, and particularly in the United States since the implementation of the MELD system in 2002. SLK transplants are considered a relatively low immunological risk procedure evidenced by multiple studies displaying the immunomodulatory properties of the liver on the immune system of SLK recipients. SLK recipients demonstrate lower rates of both cellular and antibody-mediated rejection on the kidney allograft when compared to kidney transplant-alone recipients. Therefore, SLK transplants in the setting of preformed donor-specific HLA antibodies (DSA) are a common practice, at many centers. Acceptance and transplantation of SLKs are based solely on ABO compatibility without much consideration of crossmatch results or DSA levels. However, some studies suggest an increased risk for rejection for SLK recipients transplanted across high levels of pre-formed HLA DSA. Despite this, there is no consensus regarding acceptable levels of pre-formed DSA, the role of pre-transplant desensitization, splenectomy, or immunosuppressive management in this unique population. Also, the impact of post-transplant DSA monitoring on long-term outcomes is not well-studied in SLK recipients. In this article, we review recent and relevant past articles in this field with a focus on the immunological risk factors among SLK recipients, and strategies to mitigate the negative outcomes among them.

Sugar and spice: Fc glycosylation in antibody-mediated transplant rejection

Bharadwaj etal.1 demonstrate that anti-donor HLA antibodies display low levels of Fc fucosylation. This signature was associated with potent provocation of NK cell effector functions and was discriminative for active antibody-mediated rejection among patients with donor specific HLA antibodies.

Snowflake epitope matching correlates with child-specific antibodies during pregnancy and donor-specific antibodies after kidney transplantation.

Development of donor-specific human leukocyte antigen (HLA) antibodies (DSA) remains a major risk factor for graft loss following organ transplantation, where DSA are directed towards patches on the three-dimensional structure of the respective organ donor's HLA proteins. Matching donors and recipients based on HLA epitopes appears beneficial for the avoidance of DSA. Defining surface epitopes however remains challenging and the concepts underlying their characterization are not fully understood. Based on our recently implemented computational deep learning pipeline to define HLA Class I protein-specific surface residues, we hypothesized a correlation between the number of HLA protein-specific solvent-accessible interlocus amino acid mismatches (arbitrarily called Snowflake) and the incidence of DSA. To validate our hypothesis, we considered two cohorts simultaneously. The kidney transplant cohort (KTC) considers 305 kidney-transplanted patients without DSA prior to transplantation. During the follow-up, HLA antibody screening was performed regularly to identify DSA. The pregnancy cohort (PC) considers 231 women without major sensitization events prior to pregnancy who gave live birth. Post-delivery serum was screened for HLA antibodies directed against the child's inherited paternal haplotype (CSA). Based on the involved individuals' HLA typings, the numbers of interlocus-mismatched antibody-verified eplets (AbvEPS), the T cell epitope PIRCHE-II model and Snowflake were calculated locus-specific (HLA-A, -B and -C), normalized and pooled. In both cohorts, Snowflake numbers were significantly elevated in recipients/mothers that developed DSA/CSA. Univariable regression revealed significant positive correlation between DSA/CSA and AbvEPS, PIRCHE-II and Snowflake. Snowflake numbers showed stronger correlation with numbers of AbvEPS compared to Snowflake numbers with PIRCHE-II. Our data shows correlation between Snowflake scores and the incidence of DSA after allo-immunization. Given both AbvEPS and Snowflake are B cell epitope models, their stronger correlation compared to PIRCHE-II and Snowflake appears plausible. Our data confirms that exploring solvent accessibility is a valuable approach for refining B cell epitope definitions.

Phosphorylation of S6RP in peritubular capillaries of kidney grafts and circulating HLA donor-specific antibodies.

Antibody-mediated rejection (ABMR) caused by donor-specific HLA-antibodies (DSA) is a mediator of allograft loss after kidney transplantation (KT). DSA can activate microvascular endothelium damage through the mTOR pathway. In this study we assessed the mTOR pathway activation by DSA in KT with ABMR (ABMR + DSA+) compared to controls (ABMR-DSA-), biopsies with ABMR changes without DSA (ABMR + DSA-) and DSA without ABMR changes (ABMR-DSA+), and the potential modulation by mTOR inhibitors (mTORi). We evaluated 97 biopsies: 31 ABMR + DSA+, 33 controls ABMR-DSA-, 16 ABMR + DSA-, and 17 ABMR-DSA+ cases. Regarding immunosuppression of full ABMR + DSA+ and controls, 21 biopsies were performed under mTORi treatment (11 of them ABMR + DSA+ cases) and 43 without mTORi (20 of them ABMR + DSA+) so as to explore its effect on the mTOR pathway. Biopsies were stained for C4d, Ki67, and phosphorylated (p) S6RP, ERK, and mTOR by immunohistochemistry. Labeling was graded according to peritubular capillary staining. ABMR biopsies showed significantly higher C4d, p-S6RP, and Ki67 staining in peritubular capillaries (PTC) compared to controls, and light differences in p-ERK or p-mTOR. mTORi treatment did not modify p-S6RP, p-mTOR, and p-ERK staining. Diffuse p-S6RP in PTC in the biopsies significantly associated with circulating HLA-DSA independently of graft rejection, and with worse death-censored graft survival. These findings suggest that activation of endothelium through the mTOR pathway evidence different mechanisms of damage in ABMR + DSA+ and ABMR + DSA- despite similar histological injury.

A SPECTRUM OF CAUSES OF MOLECULAR INJURY IS DETECTED BY DONOR-DERIVED CELL-FREE DNA AFTER LUNG TRANSPLANT: PRELIMINARY EXPERIENCE

A SPECTRUM OF CAUSES OF MOLECULAR INJURY IS DETECTED BY DONOR-DERIVED CELL-FREE DNA AFTER LUNG TRANSPLANT: PRELIMINARY EXPERIENCE

Cross-Talk between HLA Class I and TLR4 Mediates P-Selectin Surface Expression and Monocyte Capture to Human Endothelial Cells.

Donor-specific HLA Abs contribute to Ab-mediated rejection (AMR) by binding to HLA molecules on endothelial cells (ECs) and triggering intracellular signaling, leading to EC activation and leukocyte recruitment. The molecular mechanisms involving donor-specific HLA Ab-mediated EC activation and leukocyte recruitment remain incompletely understood. In this study, we determined whether TLRs act as coreceptors for HLA class I (HLA I) in ECs. We found that human aortic ECs express TLR3, TLR4, TLR6, and TLR10, but only TLR4 was detected on the EC surface. Consequently, we performed coimmunoprecipitation experiments to examine complex formation between HLA I and TLR4. Stimulation of human ECs with HLA Ab increased the amount of complex formation between HLA I and TLR4. Reciprocal coimmunoprecipitation with a TLR4 Ab confirmed that the crosslinking of HLA I increased complex formation between TLR4 and HLA I. Knockdown of TLR4 or MyD88 with small interfering RNAs inhibited HLA I Ab-stimulated P-selectin expression, von Willebrand factor release, and monocyte recruitment on ECs. Our results show that TLR4 is a novel coreceptor for HLA I to stimulate monocyte recruitment on activated ECs. Taken together with our previous published results, we propose that HLA I molecules form two separate signaling complexes at the EC surface, that is, with TLR4 to upregulate P-selectin surface expression and capture of monocytes to human ECs and integrin β4 to induce mTOR-dependent firm monocyte adhesion via ICAM-1 clustering on ECs, two processes implicated in Ab-mediated rejection.

Induction of Long-Lasting Regulatory B Lymphocytes by Modified Immune Cells in Kidney Transplant Recipients.

We recently demonstrated that donor-derived modified immune cells (MICs)-PBMCs that acquire immunosuppressive properties after a brief treatment-induced specific immunosuppression against the allogeneic donor when administered before kidney transplantation. We found up to a 68-fold increase in CD19 + CD24 hi CD38 hi transitional B lymphocytes compared with transplanted controls. Ten patients from a phase 1 clinical trial who had received MIC infusions before kidney transplantation were followed to post-transplant day 1080. Patients treated with MICs had a favorable clinical course, showing no donor-specific human leukocyte antigen antibodies or acute rejections. The four patients who had received the highest dose of MICs 7 days before surgery and were on reduced immunosuppressive therapy showed an absence of in vitro lymphocyte reactivity against stimulatory donor blood cells, whereas reactivity against third party cells was preserved. In these patients, numbers of transitional B lymphocytes were 75-fold and seven-fold higher than in 12 long-term survivors on minimal immunosuppression and four operationally tolerant patients, respectively ( P <0.001 for both). In addition, we found significantly higher numbers of other regulatory B lymphocyte subsets and a gene expression signature suggestive of operational tolerance in three of four patients. In MIC-treated patients, in vitro lymphocyte reactivity against donor blood cells was restored after B lymphocyte depletion, suggesting a direct pathophysiologic role of regulatory B lymphocytes in donor-specific unresponsiveness. These results indicate that donor-specific immunosuppression after MIC infusion is long-lasting and associated with a striking increase in regulatory B lymphocytes. Donor-derived MICs appear to be an immunoregulatory cell population that when administered to recipients before transplantation, may exert a beneficial effect on kidney transplants. MIC Cell Therapy for Individualized Immunosuppression in Living Donor Kidney Transplant Recipients (TOL-1), NCT02560220.

Surviving White-out: How to Manage Severe Noninfectious Acute Lung Allograft Dysfunction of Unknown Etiology.

Surviving White-out: How to Manage Severe Noninfectious Acute Lung Allograft Dysfunction of Unknown Etiology.

The natural history of de novo donor-specific HLA antibodies after kidney transplantation.

BackgroundDe novo donor-specific HLA antibodies (dnDSA) are key factors in the diagnosis of antibody-mediated rejection (ABMR) and related to graft loss.MethodsThis retrospective study was designed to evaluate the natural course of dnDSA in graft function and kidney allograft survival and to assess the impact of mean fluorescence intensity (MFI) evolution as detected by annual Luminex® screening. All 400 kidney transplant recipients with 731 dnDSA against the last graft (01/03/2000-31/05/2021) were included.ResultsDuring 8.3 years of follow-up, ABMR occurred in 24.8% and graft loss in 33.3% of the cases, especially in patients with class I and II dnDSA, and those with multiple dnDSA. We observed frequent changes in MFI with 5-year allograft survivals post-dnDSA of 74.0% in patients with MFI reduction ≥ 50%, 62.4% with fluctuating MFI (MFI reduction ≥ 50% and doubling), and 52.7% with doubling MFI (log-rank p < 0.001). Interestingly, dnDSA in 168 (24.3%) cases became negative at some point during follow-up, and 38/400 (9.5%) patients became stable negative, which was associated with better graft survival. Multivariable analysis revealed the importance of MFI evolution and rejection, while class and number of dnDSA were not contributors in this model.ConclusionIn summary, we provide an in-depth analysis of the natural course of dnDSA after kidney transplantation, first evidence for the impact of MFI evolution on graft outcomes, and describe a relevant number of patients with a stable disappearance of dnDSA, related to better allograft survival.

Cumulative mean fluorescent intensities of HLA specific antibodies predict antibody mediated rejections after kidney transplantation.

It is still not fully elucidated which pretransplant donor-specific HLA antibodies (DSA) are harmful after kidney transplantation. In particular, it needs to be clarified whether cumulative mean fluorescence intensities (MFI) against multiple HLA specificities have a predictive value for allograft function. Our retrospective single centre study analyzed preformed HLA antibodies determined by Luminex™ Single Antigen Bead (SAB) assay, including C1q addition, in relation to rejection and clinical outcome in 255 cross match negative kidney allograft recipients. Only 33 recipients (13%) of the total cohort showed early AMR during the first year posttransplant, but in patients with pre-transplant DSA the rate was increased to 15 out of 40 (38%). Three year graft survival was significantly shorter in patients with histological signs of AMR compared with patients without AMR or with no biopsy (74%, 92%, and 97%, respectively, p< 0.0001). In patients with HLA-DSA, a cumulative MFI value of all HLA antibodies of more than 103.000 indicated the highest risk for AMR posttransplant (p= 0.01). In conclusion, in patients with HLA-DSA, the cumulative MFI value may help to further stratify the risk of AMR after kidney transplantation.

Tocilizumab in the treatment of active chronic humoral rejection resistant to standard therapy

IntroductionThere is no consensus on the most appropriate treatment for chronic active antibody-mediated rejection (cAMR). Recent studies suggest that treatment with tocilizumab (TCZ) may stabilize graft function, decrease the intensity of donor-specific HLA antibodies (DSAs) and reduce inflammation of microcirculation. Patients and methodsObservational study with renal allograft recipients diagnosed with cAMR (n = 5) who had not submitted a response to traditional treatment based on the combination of plasma replacements, immunoglobulins, and rituximab. Patients were told to be treated with TCZ as compassionate use in six doses per month (8 mg/kg/month). Renal function, proteinuria, and the intensity of DSAs were monitored during follow-up. ResultsFive patients, average age 60 ± 13 years, three male and two retrasplants (cPRA average 55%) with preformed DSAs. Treatment with TCZ was initiated within 47 ± 52 days of biopsy. In two cases treatment was discontinued after the first dose, by severe bicitopenia with cytomegalovirus viremia and by graft failure, respectively. In the three patients who completed treatment, no stability of renal function (serum creatinine from 1.73 ± 0.70 to 2.04 ± 0.52 mg/dL, e-FGR 4 6 ± 15 to 36 ± 16 mL/min), showed increased proteinuria (3.2 ± 4.0 to 6.9 ± 11.0 g/g) and the intensity of DSAs maintain stable. No changes were observed in the degree of inflammation of microcirculation (g+pt 4.2 ± 0.8 vs. 4.3 ± 1.0) or in the degree of transplant glomerulopathy (cg 1.2 ± 0.4 vs. 1.8 ± 1.0). ConclusionsTCZ therapy does not appear to be effective in modifying the natural history of chronic active antibody-mediated rejection, does not improve the degree of inflammation of microcirculation and does not reduces the intensity of DSAs.

P16.07: Association Between SARS-CoV-2 Infection and de Novo HLA Donor Specific Antibody Production in Lung Transplant Recipients: Single-Center Study

Introduction: COVID-19 pandemic has led to significant morbidity and mortality in lung transplant recipients. Respiratory viral infections may be associated with de-novo HLA donor-specific antibody production and impacting lung transplant outcome. Methods: Since one of the immunomodulation strategies post-SARS-CoV-2 infection in lung transplant recipients include decreasing or holding anti-metabolites, concerns have been raised for higher incidence of de-novo HLA donor specific antibody production in lung transplant recipients. We performed a retrospective chart review of 24 consecutive lung transplant recipients diagnosed with COVID-19 to investigate this concern. Results: We observed no significant association between SARS-CoV-2 infection and immunomodulation on pre-existing or de novo HLA donor specific antibodies. Conclusion: SARS-CoV-2 infection was not associated with a significant increase in de-novo HLA DSA production or MFI levels of pre-existing HLA DSA compared to pre-COVID-19 diagnosis in lung transplant recipients. These results provide a valuable insight on the effects of SARS-CoV-2 infection on immunogenicity in lung transplant recipients.

Association between SARS-CoV-2 infection and de novo HLA donor specific antibody production in lung transplant recipients: Single-center study

The COVID-19 pandemic has led to significant morbidity and mortality in lung transplant recipients. Respiratory viral infections may be associated with de-novo HLA donor-specific antibody production and impact lung transplant outcome. Since one of the immunomodulation strategies post-SARS-CoV-2 infection in lung transplant recipients include decreasing or holding anti-metabolites, concerns have been raised for higher incidence of de-novo HLA donor specific antibody production in lung transplant recipients. We performed a retrospective chart review of 24 consecutive lung transplant recipients diagnosed with COVID-19 to investigate this concern. We observed no significant differences in the CPRA or MFI levels of HLA class I and II antibodies pre- COVID-19 compared to 1 and 6 months post-COVID-19 diagnosis in 11/24 (45.8 %) LTR (p = 0.98 and p = 0.63 respectively). HLA class I and II DSA were detected in 5/24 LTR pre-COVID-19 diagnosis and persisted with no significant differences in the median MFI levels at 1 and 6 months post-COVID-19 diagnosis (p = 0.89). De-novo HLA class I and II DSA were detected in 1/24 (4.2 %) LTR at one month post-COVID-19 diagnosis and persisted with no significant differences in the median MFI levels at 1 and 6 months post-COVID-19 diagnosis (p = 0.54). Our results suggest that there was no significant association between SARS-CoV-2 infection and immunomodulation on pre-existing or de novo HLA donor specific antibodies.

Donor specific HLA antibody in hematopoietic stem cell transplantation: Implications for donor selection.

Advances in hematopoietic stem cell transplant (HSCT) have led to changes in the approach to donor selection. Many of these new approaches result in greater HLA loci mismatching, either through the selection of haploidentical donors or permissive HLA mismatches. Although these approaches increase the potential of transplant for many patients by expanding the number of acceptable donor HLA genotypes, they add the potential barrier of donor-specific HLA antibodies (DSA). DSA presents a unique challenge in HSCT, as it can limit engraftment and lead to graft failure. However, transient reduction of HLA antibodies through desensitization treatments can limit the risk of graft failure and facilitate engraftment. Thus, the consideration of DSA in donor selection and the management of DSA prior to transplant are playing an increasingly important role in HSCT. In this review, we will discuss studies addressing the role of HLA antibodies in HSCT, the reported impact of desensitization on DSA levels, and the implications for selecting donors for patients with DSA. We found that there is a clear consensus that moderate strength DSA should be avoided, while desensitization strategies are reported to be effective in most cases at reducing DSA to amenable levels. There is limited information regarding the impact of specific characteristics of DSA, such as HLA loci or overall level of sensitization, which could further aid in donor selection for sensitized HSCT candidates.

Heart transplantation across preformed donor-specific antibody barriers using a perioperative desensitization protocol

Heart transplantation across preformed donor-specific HLA-antibody barriers is associated with impaired short- and long-term survival. Therefore, in recipients with preformed anti-HLA antibodies, waiting for crossmatch-negative donors is standard practice. As an alternative strategy, recipients with preformed anti-HLA donor specific antibodies have been managed at our institutions with a perioperative desensitization regimen. A retrospective analysis was performed comparing heart transplant recipients with preformed donor-specific HLA-antibodies to recipients without donor-specific antibodies. Recipients with a positive virtual crossmatch received a perioperative desensitization protocol including tocilizumab intraoperatively, plasma exchange and rituximab followed by a six-month course of IgGAM. Among the 117 heart-transplanted patients, 19 (16%) patients underwent perioperative desensitization, and the remaining 98 (84%) patients did not. Cold ischemic time, posttransplant extracorporeal life support for primary graft dysfunction, and intensive care unit stay time did not differ between groups. At 1-year follow-up, freedom from pulsed steroid therapy for presumed rejection and biopsy-confirmed acute cellular or humoral rejection did not differ between groups. One-year survival amounted to 94.7% in the treated patients and 81.4% in the control group. Therefore, heart transplantation in sensitized recipients undergoing a perioperative desensitization appears safe with comparable postoperative outcomes as patients with a negative crossmatch.