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Immune Monitoring Assay for Extracorporeal Photopheresis Treatment Optimization After Heart Transplantation.

Dieterlen MT , Klaeske K , Bernhardt AA , Borger MA , Klein S , Garbade J , Lehmann S , Ayuk FA , Reichenspurner H , Barten MJ
  • Frontiers in Immunology. 2021; 12:676175.
Background: Extracorporeal photopheresis (ECP) induces immunological changes that lead to a reduced risk of transplant rejection. The aim of the present study was to determine optimum conditions for ECP treatment by analyzing a variety of tolerance-inducing immune cells to optimize the treatment. Methods: Ten ECP treatments were applied to each of 17 heart-transplant patients from month 3 to month 9 post-HTx. Blood samples were taken at baseline, three times during treatment, and four months after the last ECP treatment. The abundance of subsets of tolerance-inducing regulatory T cells (Tregs) and dendritic cells (DCs) in the samples was determined by flow cytometry. A multivariate statistical model describing the immunological status of rejection-free heart transplanted patients was used to visualize the patient-specific immunological improvement induced by ECP. Results: All BDCA+ DC subsets (BDCA1+ DCs: p < 0.01, BDCA2+ DCs: p < 0.01, BDCA3+ DCs: p < 0.01, BDCA4+ DCs: p < 0.01) as well as total Tregs (p < 0.01) and CD39+ Tregs (p < 0.01) increased during ECP treatment, while CD62L+ Tregs decreased (p < 0.01). The cell surface expression level of BDCA1 (p < 0.01) and BDCA4 (p < 0.01) on DCs as well as of CD120b (p < 0.01) on Tregs increased during the study period, while CD62L expression on Tregs decreased significantly (p = 0.04). The cell surface expression level of BDCA2 (p = 0.47) and BDCA3 (p = 0.22) on DCs as well as of CD39 (p = 0.14) and CD147 (p = 0.08) on Tregs remained constant during the study period. A cluster analysis showed that ECP treatment led to a sustained immunological improvement. Conclusions: We developed an immune monitoring assay for ECP treatment after heart transplantation by analyzing changes in tolerance-inducing immune cells. This assay allowed differentiation of patients who did and did not show immunological improvement. Based on these results, we propose classification criteria that may allow optimization of the duration of ECP treatment. Copyright © 2021 Dieterlen, Klaeske, Bernhardt, Borger, Klein, Garbade, Lehmann, Ayuk, Reichenspurner and Barten.

https://pubmed.ncbi.nlm.nih.gov/34447372

BACKGROUND:
There is no standard definition for “HLA incompatible” transplants. For the first time, we systematically assessed how HLA incompatibility was defined in contemporary peer-reviewed publications and its prognostic implication to transplant outcomes.
 
METHODS:
We combined 2 independent searches of MEDLINE, EMBASE, and the Cochrane Library from 2015 to 2019. Content-expert reviewers screened for original research on outcomes of HLA-incompatible transplants (defined as allele or molecular mismatch and solid-phase or cell-based assays). We ascertained the completeness of reporting on a predefined set of variables assessing HLA incompatibility, therapies, and outcomes. Given significant heterogeneity, we conducted narrative synthesis and assessed risk of bias in studies examining the association between death-censored graft failure and HLA incompatibility.
 
RESULTS:
Of 6656 screened articles, 163 evaluated transplant outcomes by HLA incompatibility. Most articles reported on cytotoxic/flow T-cell crossmatches (n = 98). Molecular genotypes were reported for selected loci at the allele-group level. Sixteen articles reported on epitope compatibility. Pretransplant donor-specific HLA antibodies were often considered (n = 143); yet there was heterogeneity in sample handling, assay procedure, and incomplete reporting on donor-specific HLA antibodies assignment. Induction (n = 129) and maintenance immunosuppression (n = 140) were frequently mentioned but less so rejection treatment (n = 72) and desensitization (n = 70). Studies assessing death-censored graft failure risk by HLA incompatibility were vulnerable to bias in the participant, predictor, and analysis domains.
 
CONCLUSIONS:
Optimization of transplant outcomes and personalized care depends on accurate HLA compatibility assessment. Reporting on a standard set of variables will help assess generalizability of research, allow knowledge synthesis, and facilitate international collaboration in clinical trials.
 
 

Photopheresis Abates the Anti-HLA Antibody Titer and Renal Failure Progression in Chronic Antibody-Mediated Rejection.

Gregorini M , Del Fante C , Pattonieri EF , Avanzini MA , Grignano MA , Cassaniti I , Baldanti F , Comolli G , Nocco A , Ramondetta M , Viarengo G , Sepe V , Libetta C , Klersy C , Perotti C , Rampino T
  • Biology. 2021 Jun 18; 10(6).
Chronic renal antibody-mediated rejection (ABMR) is a common cause of allograft failure, but an effective therapy is not available. Extracorporeal photopheresis (ECP) has been proven successful in chronic lung and heart rejection, and graft versus host disease. The aim of this study was to evaluate the effectiveness of ECP in chronic ABMR patients. PATIENTS AND METHODS: We investigated ECP treatment in 14 patients with biopsy-proven chronic ABMR and stage 2-3 chronic renal failure. The primary aim was to e valuate the eGFR lowering after 1 year of ECP therapy. The ECP responders (R) showed eGFR reduction greater than 20% vs the basal levels. We also evaluated the effectiveness of ECP on proteinuria, anti-HLA antibodies (HLAab), interleukin 6 (IL-6) serum levels, and CD3, CD4, CD8, CD19, NK, Treg and T helper 17 (Th17) circulating cells. RESULTS: Three patients dropped out of the study. The R patients were eight (72.7%) out of the 11 remaining patients. Because ECP was not associated with any adverse reaction, the R patients continued such treatment for up to 3 years, showing a persisting eGFR stabilization. Twenty four hour proteinuria did not increase in the R patients over the follow-up when compared to the non-responder patients (NR). In the R patients, the HLAab levels were reduced and completely cleared in six out of eight patients when compared with the NR patients. The NR HLAab levels also increased after the discontinuation of the ECP. The ECP in the R patients showed a decrease in CD3, CD4, CD8, CD19, and NK circulating cells. The ECP treatment in the R patients also induced Tregs increase and Th17 cell decrease, and a decrease of the IL-6 serum levels. CONCLUSIONS: ECP abates the HLAab titer and renal failure progression in patients with chronic renal ABMR, modulating the immune cellular and humoral responses.

https://pubmed.ncbi.nlm.nih.gov/34207225

BACKGROUND:
There is no standard definition for “HLA incompatible” transplants. For the first time, we systematically assessed how HLA incompatibility was defined in contemporary peer-reviewed publications and its prognostic implication to transplant outcomes.
 
METHODS:
We combined 2 independent searches of MEDLINE, EMBASE, and the Cochrane Library from 2015 to 2019. Content-expert reviewers screened for original research on outcomes of HLA-incompatible transplants (defined as allele or molecular mismatch and solid-phase or cell-based assays). We ascertained the completeness of reporting on a predefined set of variables assessing HLA incompatibility, therapies, and outcomes. Given significant heterogeneity, we conducted narrative synthesis and assessed risk of bias in studies examining the association between death-censored graft failure and HLA incompatibility.
 
RESULTS:
Of 6656 screened articles, 163 evaluated transplant outcomes by HLA incompatibility. Most articles reported on cytotoxic/flow T-cell crossmatches (n = 98). Molecular genotypes were reported for selected loci at the allele-group level. Sixteen articles reported on epitope compatibility. Pretransplant donor-specific HLA antibodies were often considered (n = 143); yet there was heterogeneity in sample handling, assay procedure, and incomplete reporting on donor-specific HLA antibodies assignment. Induction (n = 129) and maintenance immunosuppression (n = 140) were frequently mentioned but less so rejection treatment (n = 72) and desensitization (n = 70). Studies assessing death-censored graft failure risk by HLA incompatibility were vulnerable to bias in the participant, predictor, and analysis domains.
 
CONCLUSIONS:
Optimization of transplant outcomes and personalized care depends on accurate HLA compatibility assessment. Reporting on a standard set of variables will help assess generalizability of research, allow knowledge synthesis, and facilitate international collaboration in clinical trials.
 
 

[Analysis of expression of immune system genes that are responsible for activation and inhibition of T-cell immune response in renal transplant recipients after extracorporeal photochemotherapy]

Kozlov IB , Vatazin AV , Kildushevsky AV , Zulkarnaev AB , Fedulkina VA , Faenko AP , Yazdovskiy VV , Gudima GO , Kofiadi IA
  • Immunologiya. 2020; 41(1):20-30.
Introduction. Due to the uprising need for kidney transplantation, there is a demand for new methods of preventing rejection of the transplant, based on the mechanisms of natural regulation of the immune response. One of the promising technologies in this area is extracorporeal photopheresis (ECP), based on electromagnetic influence on the recipient's cells. The clinical efficacy of ECP has been confirmed by many studies, but the mechanism of therapeutic effect has not been sufficiently studied. Characterization of immune response during ECP is an important step towards formation of practical recommendations on clinical application of ECP and modification of immunosuppressive therapy.The aim of this study was to analyze the changes in the expression level of the genes responsible for the activation and inhibition of the T-cell response in the recipients of the renal graft after ECP.Material and methods. An open cohort randomized trial was conducted with 20 patients who underwent a single group cadaver kidney transplantation from an unrelated donor. The recipients of the compared groups received standard immunosuppressive therapy and the same therapy in combination with ECP procedures, according to the study protocol. The level of gene expression was analyzed by real-time RT-PCR. Comparison of the study groups was carried out in point 1 (1st-4th day) and point 2 (30th day). Results. The study of organ function in recipients of paired kidney allograft who received standard immunosupressive therapy and therapy in combination with ECP was carried out. The analysis of clinical data did not show statistically significant clinical differences, but in the specific consideration of each pair of cases the tendency to some improvement of the transplant organ engraftment rate in the early terms after the transplant, better survival of the graft and the recipient was revealed. The level of expression of genes involved in immune response regulation (CD28, CTLA4, PDL1, FOXP3) and cytokine genes (TNFA, IL1, IL2, IL10, IFNG) in the studied groups was determined. Conclusion. According to the results of comparative analysis the level of expression of pro-inflammatory cytokines' genes IL1, IL2 and IFNG decreased to 30th day after transplantation. A 30-day comparison between groups shows an increase in the expression level of the PDL1 and FOXP3 genes (p = 0.0009 and 0.0013, correspondingly). Increased expression of these genes may be associated with the activation of regulatory T-cells and the development of peripheral tolerance.

https://www.immunologiya-journal.ru/en/jarticles_immunology/66.html

BACKGROUND:
There is no standard definition for “HLA incompatible” transplants. For the first time, we systematically assessed how HLA incompatibility was defined in contemporary peer-reviewed publications and its prognostic implication to transplant outcomes.
 
METHODS:
We combined 2 independent searches of MEDLINE, EMBASE, and the Cochrane Library from 2015 to 2019. Content-expert reviewers screened for original research on outcomes of HLA-incompatible transplants (defined as allele or molecular mismatch and solid-phase or cell-based assays). We ascertained the completeness of reporting on a predefined set of variables assessing HLA incompatibility, therapies, and outcomes. Given significant heterogeneity, we conducted narrative synthesis and assessed risk of bias in studies examining the association between death-censored graft failure and HLA incompatibility.
 
RESULTS:
Of 6656 screened articles, 163 evaluated transplant outcomes by HLA incompatibility. Most articles reported on cytotoxic/flow T-cell crossmatches (n = 98). Molecular genotypes were reported for selected loci at the allele-group level. Sixteen articles reported on epitope compatibility. Pretransplant donor-specific HLA antibodies were often considered (n = 143); yet there was heterogeneity in sample handling, assay procedure, and incomplete reporting on donor-specific HLA antibodies assignment. Induction (n = 129) and maintenance immunosuppression (n = 140) were frequently mentioned but less so rejection treatment (n = 72) and desensitization (n = 70). Studies assessing death-censored graft failure risk by HLA incompatibility were vulnerable to bias in the participant, predictor, and analysis domains.
 
CONCLUSIONS:
Optimization of transplant outcomes and personalized care depends on accurate HLA compatibility assessment. Reporting on a standard set of variables will help assess generalizability of research, allow knowledge synthesis, and facilitate international collaboration in clinical trials.
 
 

Extracorporeal photopheresis and renal transplantation

Granados S.F. , Tagarro E.F. , Puga A.R. , Rodriguez R.G. , Saavedra I.A. , Nuez S.G. , Garcia-Canton C. , Fuertes F.F. , Martin M.T.
  • Nefrologia. 2020 Nov 01; 40(6) :687-689.
No abstract available

https://pubmed.ncbi.nlm.nih.gov/32317125

BACKGROUND:
There is no standard definition for “HLA incompatible” transplants. For the first time, we systematically assessed how HLA incompatibility was defined in contemporary peer-reviewed publications and its prognostic implication to transplant outcomes.
 
METHODS:
We combined 2 independent searches of MEDLINE, EMBASE, and the Cochrane Library from 2015 to 2019. Content-expert reviewers screened for original research on outcomes of HLA-incompatible transplants (defined as allele or molecular mismatch and solid-phase or cell-based assays). We ascertained the completeness of reporting on a predefined set of variables assessing HLA incompatibility, therapies, and outcomes. Given significant heterogeneity, we conducted narrative synthesis and assessed risk of bias in studies examining the association between death-censored graft failure and HLA incompatibility.
 
RESULTS:
Of 6656 screened articles, 163 evaluated transplant outcomes by HLA incompatibility. Most articles reported on cytotoxic/flow T-cell crossmatches (n = 98). Molecular genotypes were reported for selected loci at the allele-group level. Sixteen articles reported on epitope compatibility. Pretransplant donor-specific HLA antibodies were often considered (n = 143); yet there was heterogeneity in sample handling, assay procedure, and incomplete reporting on donor-specific HLA antibodies assignment. Induction (n = 129) and maintenance immunosuppression (n = 140) were frequently mentioned but less so rejection treatment (n = 72) and desensitization (n = 70). Studies assessing death-censored graft failure risk by HLA incompatibility were vulnerable to bias in the participant, predictor, and analysis domains.
 
CONCLUSIONS:
Optimization of transplant outcomes and personalized care depends on accurate HLA compatibility assessment. Reporting on a standard set of variables will help assess generalizability of research, allow knowledge synthesis, and facilitate international collaboration in clinical trials.
 
 

Outcome of Extracorporeal Photopheresis as an Add-On Therapy for Antibody-Mediated Rejection in Lung Transplant Recipients.

Benazzo A , Worel N , Schwarz S , Just U , Nechay A , Lambers C , Bohmig G , Fischer G , Koren D , Murakozy G , Knobler R , Klepetko W , Hoetzenecker K , Jaksch P
  • Transfusion Medicine & Hemotherapy. 2020 Jun; 47(3):205-213.
INTRODUCTION: The diagnosis and treatment of antibody-mediated rejection (AMR) after lung transplantation has recently gained recognition within the transplant community. Extracorporeal photopheresis (ECP), currently used to treat chronic lung allograft dysfunction, modulates various pathways of the immune system known to be involved in AMR. We hypothesize that adding ECP to established AMR treatments could prevent the rebound of donor-specific antibodies (DSA). OBJECTIVES: This study aimed to analyze the role of ECP as an add-on therapy to prevent the rebound of DSA. METHODS: Lung transplant recipients who received ECP as an add-on therapy for pulmonary AMR between January 2010 and January 2019 were included in this single-center retrospective analysis. Baseline demographics of the patients, as well as their immunological characteristics and long-term transplant outcomes, were analyzed. RESULTS: A total of 41 patients developed clinical AMR during the study period. Sixteen patients received ECP as an add-on therapy after first-line AMR treatment. Among the 16 patients, 2 (13%) had pretransplant DSA, both against human leukocyte antigen (HLA) class I (B38, B13, and C06). Fifteen patients (94%) developed de novo DSA (dnDSA), i.e., 10 (63%) against class I and 14 (88%) against class II. The median time to dnDSA after lung transplantation was 361 days (range 25-2,548). According to the most recent International Society of Heart and Lung Transplantation (ISHLT) consensus report, 2 (13%) patients had definite clinical AMR, 6 (38%) had probable AMR, and 7 (44%) had possible AMR. The median mean fluorescence intensity (MFI) of dnDSA at the time of clinical diagnosis was 4,220 (range 1,319-10,552) for anti-HLA class I and 10,953 (range 1,969-27,501) for anti-HLA class II antibodies. ECP was performed for a median of 14 cycles (range 1-64). MFI values of dnDSA against HLA classes I and II were significantly reduced over the treatment period (for anti-class I: 752; range 70-2,066; for anti-class II: 5,612; range 1,689-21,858). The 1-year survival rate was 55%. No adverse events related to ECP were reported in any of the patients. CONCLUSIONS: ECP is associated with a reduction of dnDSA in lung transplant recipients affected by AMR. Prospective studies are warranted to confirm the beneficial effects of ECP in the setting of AMR. Copyright © 2020 by S. Karger AG, Basel.

https://pubmed.ncbi.nlm.nih.gov/32595425

BACKGROUND:
There is no standard definition for “HLA incompatible” transplants. For the first time, we systematically assessed how HLA incompatibility was defined in contemporary peer-reviewed publications and its prognostic implication to transplant outcomes.
 
METHODS:
We combined 2 independent searches of MEDLINE, EMBASE, and the Cochrane Library from 2015 to 2019. Content-expert reviewers screened for original research on outcomes of HLA-incompatible transplants (defined as allele or molecular mismatch and solid-phase or cell-based assays). We ascertained the completeness of reporting on a predefined set of variables assessing HLA incompatibility, therapies, and outcomes. Given significant heterogeneity, we conducted narrative synthesis and assessed risk of bias in studies examining the association between death-censored graft failure and HLA incompatibility.
 
RESULTS:
Of 6656 screened articles, 163 evaluated transplant outcomes by HLA incompatibility. Most articles reported on cytotoxic/flow T-cell crossmatches (n = 98). Molecular genotypes were reported for selected loci at the allele-group level. Sixteen articles reported on epitope compatibility. Pretransplant donor-specific HLA antibodies were often considered (n = 143); yet there was heterogeneity in sample handling, assay procedure, and incomplete reporting on donor-specific HLA antibodies assignment. Induction (n = 129) and maintenance immunosuppression (n = 140) were frequently mentioned but less so rejection treatment (n = 72) and desensitization (n = 70). Studies assessing death-censored graft failure risk by HLA incompatibility were vulnerable to bias in the participant, predictor, and analysis domains.
 
CONCLUSIONS:
Optimization of transplant outcomes and personalized care depends on accurate HLA compatibility assessment. Reporting on a standard set of variables will help assess generalizability of research, allow knowledge synthesis, and facilitate international collaboration in clinical trials.
 
 

[Immunological monitoring of the efficacy of extracorporeal photopheresis for prevention of kidney transplant rejection].

Faenko AP , Chuksina YY , Zulkarnayev AB , Fedulkina VA , Vatazin AV , Kantaria RO
  • Urologiia (Moscow, Russia). 2020 Sep; (4)73-78.
BACKGROUND: The concept of the formation of immunological tolerance is a promising direction for correcting the renal transplant rejection. One of these methods is extracorporeal photochemotherapy (ECP), however, according to the literature, there is no single concept of its mechanisms of action in the formation of immunological tolerance in transplantology. AIM: To assess the effect of the preventive use of extracorporeal photochemotherapy on the factors of cellular immunity that contribute to the development of long-term tolerance in patients after kidney transplantation. MATERIALS AND METHODS: A total of 24 patients after a cadaveric kidney transplantation with group matching were included in the study. During the first six months after transplantation, 15 patients of the main group (MG) underwent 10 sessions of ECP in combination with the standard immunosuppression protocol, and 9 patients of the control group (CG) received only standard immunosuppressive therapy. Immunological studies were carried out by the 3rd year after transplantation. The number of cells expressing the antigens CD3, CD4, CD8, CD19, CD16 and CD56, the expression of co-stimulating molecules CD25, CD28 on T-lymphocytes, the number of T-regulatory cells with the CD3+ CD4+ CD25+ (hi) CD127- phenotype was evaluated. RESULTS: Compared with early post-transplant period, the number of naive CD3+CD4+CD45RO-CD28+ T-cells and CD28+ antigen expression was not different between two groups by 3 years after transplantation and with a group of otherwise healthy individuals (p=0.47 and p=0.26, respectively). Three years after transplantation, the T-helper lymphocyte count (CD3+CD4+) in MG were significantly higher than in CG (48.5+/-7.3% vs. 43.0+/-4.6%, respectively; p=0,04), cytotoxic T-lymphocytes count (CD3+CD8+) was 29.5+/-8.9% in MG, compared to 36.1+/-8.6% in CG (p=0.09), the ratio of CD4+/CD8+ in MG was significantly higher (1.83+/-0.72) than in CG (1.29+/-0.49) (p=0.04). CD19+ lymphocytes count was significantly below normal values in both groups, but in the CG it was more pronounced than in the MG (5.06+/-2.1% and 7.73+/-3%, respectively, (p=0.02) In the long-term period, CD3+CD4+CD25+(hi)CD127- T-regulatory cells count in MG was significantly higher than in CG (20.6+/-10.76*106/L and 12.9+/-4.97*106/l, respectively) (p=0.04). CONCLUSION: ECP initiates immunological tolerance through the activation of a second co-activation pathway between B-7 and CTLA-4 molecules in the early period after kidney transplantation. As a result, a clone of tolerogenic CD3+CD4+ T-lymphocytes is formed, which differentiates into T-regulatory cells and maintains immunological tolerance in the long-term period. Using ECP as a part of combination therapy allows to normalize the indicators of cellular immunity in the long-term period. BACKGROUND: The concept of the formation of immunological tolerance is a promising direction for correcting the renal transplant rejection. One of these methods is extracorporeal photochemotherapy (ECP), however, according to the literature, there is no single concept of its mechanisms of action in the formation of immunological tolerance in transplantology. AIM: To assess the effect of the preventive use of extracorporeal photochemotherapy on the factors of cellular immunity that contribute to the development of long-term tolerance in patients after kidney transplantation. MATERIALS AND METHODS: A total of 24 patients after a cadaveric kidney transplantation with group matching were included in the study. During the first six months after transplantation, 15 patients of the main group (MG) underwent 10 sessions of ECP in combination with the standard immunosuppression protocol, and 9 patients of the control group (CG) received only standard immunosuppressive therapy. Immunological studies were carried out by the 3rd year after transplantation. The number of cells expressing the antigens CD3, CD4, CD8, CD19, CD16 and CD56, the expression of co-stimulating molecules CD25, CD28 on T-lymphocytes, the number of T-regulatory cells with the CD3+ CD4+ CD25+ (hi) CD127- phenotype was evaluated. RESULTS: Compared with early post-transplant period, the number of naive CD3+CD4+CD45RO-CD28+ T-cells and CD28+ antigen expression was not different between two groups by 3 years after transplantation and with a group of otherwise healthy individuals (p=0.47 and p=0.26, respectively). Three years after transplantation, the T-helper lymphocyte count (CD3+CD4+) in MG were significantly higher than in CG (48.5+/-7.3% vs. 43.0+/-4.6%, respectively; p=0,04), cytotoxic T-lymphocytes count (CD3+CD8+) was 29.5+/-8.9% in MG, compared to 36.1+/-8.6% in CG (p=0.09), the ratio of CD4+/CD8+ in MG was significantly higher (1.83+/-0.72) than in CG (1.29+/-0.49) (p=0.04). CD19+ lymphocytes count was significantly below normal values in both groups, but in the CG it was more pronounced than in the MG (5.06+/-2.1% and 7.73+/-3%, respectively, (p=0.02) In the long-term period, CD3+CD4+CD25+(hi)CD127- T-regulatory cells count in MG was significantly higher than in CG (20.6+/-10.76*106/L and 12.9+/-4.97*106/l, respectively) (p=0.04). CONCLUSION: ECP initiates immunological tolerance through the activation of a second co-activation pathway between B-7 and CTLA-4 molecules in the early period after kidney transplantation. As a result, a clone of tolerogenic CD3+CD4+ T-lymphocytes is formed, which differentiates into T-regulatory cells and maintains immunological tolerance in the long-term period. Using ECP as a part of combination therapy allows to normalize the indicators of cellular immunity in the long-term period.

https://pubmed.ncbi.nlm.nih.gov/32897018

BACKGROUND:
There is no standard definition for “HLA incompatible” transplants. For the first time, we systematically assessed how HLA incompatibility was defined in contemporary peer-reviewed publications and its prognostic implication to transplant outcomes.
 
METHODS:
We combined 2 independent searches of MEDLINE, EMBASE, and the Cochrane Library from 2015 to 2019. Content-expert reviewers screened for original research on outcomes of HLA-incompatible transplants (defined as allele or molecular mismatch and solid-phase or cell-based assays). We ascertained the completeness of reporting on a predefined set of variables assessing HLA incompatibility, therapies, and outcomes. Given significant heterogeneity, we conducted narrative synthesis and assessed risk of bias in studies examining the association between death-censored graft failure and HLA incompatibility.
 
RESULTS:
Of 6656 screened articles, 163 evaluated transplant outcomes by HLA incompatibility. Most articles reported on cytotoxic/flow T-cell crossmatches (n = 98). Molecular genotypes were reported for selected loci at the allele-group level. Sixteen articles reported on epitope compatibility. Pretransplant donor-specific HLA antibodies were often considered (n = 143); yet there was heterogeneity in sample handling, assay procedure, and incomplete reporting on donor-specific HLA antibodies assignment. Induction (n = 129) and maintenance immunosuppression (n = 140) were frequently mentioned but less so rejection treatment (n = 72) and desensitization (n = 70). Studies assessing death-censored graft failure risk by HLA incompatibility were vulnerable to bias in the participant, predictor, and analysis domains.
 
CONCLUSIONS:
Optimization of transplant outcomes and personalized care depends on accurate HLA compatibility assessment. Reporting on a standard set of variables will help assess generalizability of research, allow knowledge synthesis, and facilitate international collaboration in clinical trials.
 
 

Extracorporeal photopheresis for the treatment of graft rejection in 33 adult kidney transplant recipients.

Tamain M , Sayegh J , Lionet A , Grimbert P , Philipponnet C , Hazzan M , Augusto JF , Buchler M , Merlin E , Kosmadakis G , Tiple A , Pereira B , Garrouste C , Heng AE
  • Transfusion & Apheresis Science. 2019 Aug; 58(4):515-524.
Background - Extracorporeal photopheresis (ECP) has shown encouraging results in the prevention of allograft rejection in heart transplantation. However, the role of ECP in kidney transplant (KT) rejection needs to be determined. Methods - This multicentre retrospective study included 33 KT recipients who were treated with ECP for allograft rejection (23 acute antibody-mediated rejections (AMRs), 2 chronic AMRs and 8 acute cellular rejections (ACRs)). The ECP indications were KT rejection in patients who were resistant to standard therapies (n=18) or in patients for whom standard therapies were contraindicated because of concomitant infections or cancers (n=15). Results - At 12 months (M12) post-ECP, 11 patients (33%) had a stabilization of kidney function with a graft survival rate of 61%. The Banff AMR score (g+ptc+v) was a risk factor for graft loss at M12 (HR 1.44 [1.01-2.05], p<0.05). The factorial mixed data analysis identified 2 clusters. Patients with a functional graft at M12 tended to have cellular and/or chronic rejections. Patients with graft loss at M12 tended to have acute rejections and/or AMR; higher serum creatinine levels; DSA levels and histologic scores of AMR; and a longer delay between the rejection and ECP start than those of patients with functional grafts. Conclusions - ECP may be helpful to control ACR or moderate AMR in KT recipients presenting concomitant opportunistic infections or malignancies when it is initiated early. Copyright © 2019 Elsevier Ltd. All rights reserved.

https://pubmed.ncbi.nlm.nih.gov/31383541

BACKGROUND:
There is no standard definition for “HLA incompatible” transplants. For the first time, we systematically assessed how HLA incompatibility was defined in contemporary peer-reviewed publications and its prognostic implication to transplant outcomes.
 
METHODS:
We combined 2 independent searches of MEDLINE, EMBASE, and the Cochrane Library from 2015 to 2019. Content-expert reviewers screened for original research on outcomes of HLA-incompatible transplants (defined as allele or molecular mismatch and solid-phase or cell-based assays). We ascertained the completeness of reporting on a predefined set of variables assessing HLA incompatibility, therapies, and outcomes. Given significant heterogeneity, we conducted narrative synthesis and assessed risk of bias in studies examining the association between death-censored graft failure and HLA incompatibility.
 
RESULTS:
Of 6656 screened articles, 163 evaluated transplant outcomes by HLA incompatibility. Most articles reported on cytotoxic/flow T-cell crossmatches (n = 98). Molecular genotypes were reported for selected loci at the allele-group level. Sixteen articles reported on epitope compatibility. Pretransplant donor-specific HLA antibodies were often considered (n = 143); yet there was heterogeneity in sample handling, assay procedure, and incomplete reporting on donor-specific HLA antibodies assignment. Induction (n = 129) and maintenance immunosuppression (n = 140) were frequently mentioned but less so rejection treatment (n = 72) and desensitization (n = 70). Studies assessing death-censored graft failure risk by HLA incompatibility were vulnerable to bias in the participant, predictor, and analysis domains.
 
CONCLUSIONS:
Optimization of transplant outcomes and personalized care depends on accurate HLA compatibility assessment. Reporting on a standard set of variables will help assess generalizability of research, allow knowledge synthesis, and facilitate international collaboration in clinical trials.
 
 

Factors Associated With Mortality and Response to Extracorporeal Photopheresis in Lung Allograft Recipients With Bronchiolitis Obliterans Syndrome.

Karnes HE , Schindler EI , Morrell M , Hachem RR , Berman K , Vedantham S , Atkinson J , Spitznagel E , Despotis GJ
  • Transplantation. 2019; 103(5):1036-1042.
BACKGROUND: This study was designed to identify factors associated with clinical response to extracorporeal photopheresis (ECP) and mortality after ECP in lung allograft recipients with bronchiolitis obliterans. METHODS: Forced expiratory volume in 1 second (FEV1) values obtained 6 months before (baseline) and 6 months after initiation of ECP were used to plot the linear relationship between FEV1 versus time before and after ECP. Response to ECP was assigned when a positive integer was derived after subtracting the baseline rate of decline from the rate of decline 6 months after ECP. Univariate and multivariate logistic regression analyses were used to identify demographic, treatment-related factors or spirometric parameters that may be associated with response to ECP or mortality at either 6 or 16 months after initiation of ECP. RESULTS: Forced expiratory volume in 1 second just before ECP was associated with mortality (P = 0.007) at 16 months after ECP initiation. An FEV1 of 1.50 L or less had a sensitivity of 87% and specificity of 60% to identify patients who died within 16 months after ECP initiation. Patients whose FEV1 decline exceeded 40 mL/month were 12 times more likely to have a response to ECP (P = 0.0001). Patients whose decline in FEV1 before ECP was statistically significant (P < 0.05) were nearly 10 times (P = 0.008) more likely to respond to ECP. CONCLUSIONS: Forced expiratory volume in 1 second is an important predictor of mortality, and the response to ECP is influenced by both the extent (>40 mL/mo) and statistical significance of the relationship between FEV1 versus time before ECP initiation. Therefore, earlier bronchiolitis obliterans detection and more timely implementation of ECP (ie, when FEV1 values >1.5 L) should be considered especially in patients with a more aggressive rate of decline of lung function.

https://pubmed.ncbi.nlm.nih.gov/30130331

BACKGROUND:
There is no standard definition for “HLA incompatible” transplants. For the first time, we systematically assessed how HLA incompatibility was defined in contemporary peer-reviewed publications and its prognostic implication to transplant outcomes.
 
METHODS:
We combined 2 independent searches of MEDLINE, EMBASE, and the Cochrane Library from 2015 to 2019. Content-expert reviewers screened for original research on outcomes of HLA-incompatible transplants (defined as allele or molecular mismatch and solid-phase or cell-based assays). We ascertained the completeness of reporting on a predefined set of variables assessing HLA incompatibility, therapies, and outcomes. Given significant heterogeneity, we conducted narrative synthesis and assessed risk of bias in studies examining the association between death-censored graft failure and HLA incompatibility.
 
RESULTS:
Of 6656 screened articles, 163 evaluated transplant outcomes by HLA incompatibility. Most articles reported on cytotoxic/flow T-cell crossmatches (n = 98). Molecular genotypes were reported for selected loci at the allele-group level. Sixteen articles reported on epitope compatibility. Pretransplant donor-specific HLA antibodies were often considered (n = 143); yet there was heterogeneity in sample handling, assay procedure, and incomplete reporting on donor-specific HLA antibodies assignment. Induction (n = 129) and maintenance immunosuppression (n = 140) were frequently mentioned but less so rejection treatment (n = 72) and desensitization (n = 70). Studies assessing death-censored graft failure risk by HLA incompatibility were vulnerable to bias in the participant, predictor, and analysis domains.
 
CONCLUSIONS:
Optimization of transplant outcomes and personalized care depends on accurate HLA compatibility assessment. Reporting on a standard set of variables will help assess generalizability of research, allow knowledge synthesis, and facilitate international collaboration in clinical trials.
 
 

The efficacy of extracorporeal photopheresis to arrest bronchiolitis obliterans in lung allograft recipients was compared between two automated photopheresis instruments.

Chionis L , Grossman BJ , Hachem R , Commean P , Derfler MC , Vedantham S , Dodds K , Spitznagel E , Atkinson J , Despotis G
  • Transfusion. 2018; 58(12):2933-2941.
BACKGROUND: The most common instruments used for extracorporeal photopheresis (ECP) treatment in the United States are the UVAR XTS and the CELLEX devices (Therakos, West Chester, PA). When compared to the UVAR XTS instrument, the efficacy of the CELLEX instrument to arrest the decline in lung function in patients with chronic lung allograft dysfunction (CLAD) related to bronchiolitis obliterans (BOS) has not been previously evaluated. METHODS: The relative efficacy of the CELLEX vs UVAR XTS ECP instruments was assessed by comparing the difference in rates of FEV1 decline before and after ECP treatment and survival in two series of lung allograft recipients with BOS who had been treated with these instruments. RESULTS: Similar Slope Difference values for change in rate of decline (6 months Post ECP - Pre ECP) were observed between the two cohorts (UVAR XTS: 85 +/- 109 mL/month vs CELLEX: 76 +/- 128 mL/month, p=0.72). A similar percentage of patients responded to ECP (UVAR XTS: 77% vs CELLEX: 89%; p=0.36) i.e., as defined as a positive difference in slope between the rate of decline of FEV1 before and 6 months after ECP. Survival at either 6 (p=0.89) or 12 (p=0.8) months after the start of ECP was not associated with instrument used despite a trend in higher early mortality (34% vs 17%, p=0.054) in the patients who were predominately treated with the CELLEX. CONCLUSIONS: Our data support the use of the CELLEX for prospective studies designed to evaluate the merits of ECP in this population. Copyright © 2018 AABB.

https://pubmed.ncbi.nlm.nih.gov/30312482

BACKGROUND:
There is no standard definition for “HLA incompatible” transplants. For the first time, we systematically assessed how HLA incompatibility was defined in contemporary peer-reviewed publications and its prognostic implication to transplant outcomes.
 
METHODS:
We combined 2 independent searches of MEDLINE, EMBASE, and the Cochrane Library from 2015 to 2019. Content-expert reviewers screened for original research on outcomes of HLA-incompatible transplants (defined as allele or molecular mismatch and solid-phase or cell-based assays). We ascertained the completeness of reporting on a predefined set of variables assessing HLA incompatibility, therapies, and outcomes. Given significant heterogeneity, we conducted narrative synthesis and assessed risk of bias in studies examining the association between death-censored graft failure and HLA incompatibility.
 
RESULTS:
Of 6656 screened articles, 163 evaluated transplant outcomes by HLA incompatibility. Most articles reported on cytotoxic/flow T-cell crossmatches (n = 98). Molecular genotypes were reported for selected loci at the allele-group level. Sixteen articles reported on epitope compatibility. Pretransplant donor-specific HLA antibodies were often considered (n = 143); yet there was heterogeneity in sample handling, assay procedure, and incomplete reporting on donor-specific HLA antibodies assignment. Induction (n = 129) and maintenance immunosuppression (n = 140) were frequently mentioned but less so rejection treatment (n = 72) and desensitization (n = 70). Studies assessing death-censored graft failure risk by HLA incompatibility were vulnerable to bias in the participant, predictor, and analysis domains.
 
CONCLUSIONS:
Optimization of transplant outcomes and personalized care depends on accurate HLA compatibility assessment. Reporting on a standard set of variables will help assess generalizability of research, allow knowledge synthesis, and facilitate international collaboration in clinical trials.
 
 

Comparison of extracorporeal photopheresis and alemtuzumab for the treatment of chronic lung allograft dysfunction.

Moniodis A , Townsend K , Rabin A , Aloum O , Stempel J , Burkett P , Camp P , Divo M , El-Chemaly S , Mallidi H , Rosas I , Fuhlbrigge A , Koo S , Goldberg HJ
  • Journal of Heart & Lung Transplantation. 2018; 37(3):340-348.
BACKGROUND: Survival after lung transplantation is limited by chronic lung allograft dysfunction (CLAD). Immunomodulatory therapies such as extracorporeal photopheresis (ECP) and alemtuzumab (AL) have been described for refractory CLAD, but comparative outcomes are not well defined. METHODS: We retrospectively reviewed spirometric values and clinical outcomes after therapy with ECP, AL, or no treatment (NT) in patients with CLAD who underwent transplant between January 2005 and December 2014. We used inverse probability-weighted regression adjustment (IPWRA) to adjust for potential confounders affecting treatment choice. RESULTS: Of 267 patients, 31 received immunomodulatory therapies for CLAD, and 78 received NT. The slope of forced expiratory volume in 1 second (FEV1) decline significantly improved after treatment with AL and with ECP compared with pre-treatment FEV1 slope; however, there was no significant change in slope of forced vital capacity (FVC). Comparison with NT was limited because of clinical differences in treatment groups. After IPWRA, we found no significant difference in mean difference of FEV1 slope (ml/month) when comparing treatment with NT, suggesting stabilization of lung function in the treatment group. We found no difference between the 2 immunomodulatory therapies 1, 3, and 6 months post-treatment (-49.9 [95% CI -581.8, +482.0], p = 0.85; +27.7 [95% CI -167.6, +223.0], p = 0.78; -9.6 [95% CI -167.5, +148.2], p = 0.91). We found no difference in mean FVC slope or differences between ECP and AL in infection rates or survival after treatment. CONCLUSIONS: Immunomodulatory therapy for CLAD with ECP or AL was associated with a significant change in FEV1 slope post-treatment compared with pre-treatment slope, with minimal effect on FVC. There was no difference between the 2 therapies in their effect on pulmonary function. Copyright © 2018 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

https://pubmed.ncbi.nlm.nih.gov/28431983

BACKGROUND:
There is no standard definition for “HLA incompatible” transplants. For the first time, we systematically assessed how HLA incompatibility was defined in contemporary peer-reviewed publications and its prognostic implication to transplant outcomes.
 
METHODS:
We combined 2 independent searches of MEDLINE, EMBASE, and the Cochrane Library from 2015 to 2019. Content-expert reviewers screened for original research on outcomes of HLA-incompatible transplants (defined as allele or molecular mismatch and solid-phase or cell-based assays). We ascertained the completeness of reporting on a predefined set of variables assessing HLA incompatibility, therapies, and outcomes. Given significant heterogeneity, we conducted narrative synthesis and assessed risk of bias in studies examining the association between death-censored graft failure and HLA incompatibility.
 
RESULTS:
Of 6656 screened articles, 163 evaluated transplant outcomes by HLA incompatibility. Most articles reported on cytotoxic/flow T-cell crossmatches (n = 98). Molecular genotypes were reported for selected loci at the allele-group level. Sixteen articles reported on epitope compatibility. Pretransplant donor-specific HLA antibodies were often considered (n = 143); yet there was heterogeneity in sample handling, assay procedure, and incomplete reporting on donor-specific HLA antibodies assignment. Induction (n = 129) and maintenance immunosuppression (n = 140) were frequently mentioned but less so rejection treatment (n = 72) and desensitization (n = 70). Studies assessing death-censored graft failure risk by HLA incompatibility were vulnerable to bias in the participant, predictor, and analysis domains.
 
CONCLUSIONS:
Optimization of transplant outcomes and personalized care depends on accurate HLA compatibility assessment. Reporting on a standard set of variables will help assess generalizability of research, allow knowledge synthesis, and facilitate international collaboration in clinical trials.
 
 
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