Monitoring Pharmacologically Induced Immunosuppression by Immune Repertoire Sequencing to Detect Acute Allograft Rejection in Heart Transplant Patients: A Proof-of-Concept Diagnostic Accuracy Study

Vollmers, Christopher; Vlaminck, Iwijn De; Valantine, Hannah A.; Penland, Lolita; Luikart, Helen; Strehl, Calvin; Cohen, Garrett; Khush, Kiran K.; Quake, Stephen R.

doi:10.1371/journal.pmed.1001890

Cited by 22 publications

(21 citation statements)

References 29 publications

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“…This observation raises the question of whether TTV load can be used to gauge immunocompetence. Consistent with this hypothesis are recent studies demonstrating the association between TTV viral loads and rejection (16*, 18*) (Figure 1) as well as opportunistic infection. (19)…”

Section: Introductionsupporting

confidence: 82%

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Personalized treatment in heart transplantation

Khush

2017

Current Opinion in Organ Transplantation

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Purpose of review We are entering the era of personalized medicine, in which pharmacogenomics and biomarker-based assays can be used to tailor diagnostic tests and drug therapies to individual patients. This new approach to patient-specific care offers the potential to maximize the efficacy of available medical treatments while reducing the incidence of adverse side effects. Here we present approaches to personalize the care of heart transplant recipients. Recent findings Four strategies for personalized post-transplant care are described, including (1) use of pharmacogenomic data to individualize the use of immunosuppressive drugs, (2) immune monitoring to prevent acute rejection while reducing the long-term consequences of over-immunosuppression, (3) non-invasive surveillance for acute rejection, and (4) targeted prophylaxis against opportunistic infections. Summary The long-term survival of heart transplant recipients is limited by side effects of immunosuppressive drugs, including infectious complications, renal dysfunction, and malignancy. We discuss strategies to maximize the benefits of immunosuppressive and prophylactic therapies while minimizing their long-term toxicities.

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Section: Introductionsupporting

confidence: 82%

“…(18*) The antibody heavy chain IGH transcript is unique as its expression changes in abundance and in sequence when a B cell is activated. Activated B cells express high levels of mutated antibodies of the IgG and IgA isotypes, while naïve B cells express non-mutated IgM antibodies at low levels.…”

Section: Introductionmentioning

confidence: 99%

Personalized treatment in heart transplantation

Khush

2017

Current Opinion in Organ Transplantation

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“…The human immune system relies on highly diverse and complex receptors to protect us from a wide array of pathogens. The transcripts encoding these immune receptors are of great interest to basic and translational research as well as diagnostic and other clinical purposes 5,11,12 . However, RNA-seq, the current gold-standard for whole transcriptome analysis, fails short of describing these immune receptors completely and accurately 7 .…”

Section: Introductionmentioning

confidence: 99%

Complete characterization of the human immune cell transcriptome using accurate full-length cDNA sequencing

Cole

Byrne

Adams

et al. 2019

Preprint

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ABSTRACTThe human immune system relies on highly complex and diverse transcripts and the proteins they encode. These include transcripts for Human Leukocyte Antigen (HLA) class I and II receptors which are essential for self/non-self discrimination by the immune system as well as transcripts encoding B cell and T cell receptors (BCR and TCR) which recognize, bind, and help eliminate foreign antigens.HLA genes are highly diverse within the human population with each individual possessing two of thousands of different alleles in each of the 9 major HLA genes. Determining which combination of alleles an individual possesses for each HLA gene (high-resolution HLA-typing) is essential to establish donor-recipient compatibility in organ and bone-marrow transplantations. BCR and TCR genes in turn are generated by recombining a diverse set of gene segments on the DNA level in each maturing B and T cell, respectively. This process generates adaptive immune receptor repertoires (AIRR) of composed of unique transcripts expressed by each B and T cells. These repertoires carry a vast amount of health relevant information. Both short-read RNA-seq based HLA-typing1 and adaptive immune receptor repertoire sequencing2–5 currently rely heavily on our incomplete knowledge of the genetic diversity at HLA6 and BCR/TCR loci7,8.Here we used our nanopore sequencing based Rolling Circle toConcatemeric Consensus (R2C2) protocol9 to generate over 10,000,000 full-length cDNA sequences at a median accuracy of 97.9%. We used this dataset to demonstrate that deep and accurate full-length cDNA sequencing can - in addition to providing isoform-level transcriptome analysis for over 9,000 loci - be used to generate accurate sequences of HLA alleles for HLA allele typing and discovery as well as detailed AIRR data for the analysis of the adaptive immune system without requiring specific knowledge of the diversity at HLA and BCR/TCR loci.

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“…High-throughput DNA sequencing of immunoglobulin genes has been used to detect and follow residual disease in B cell malignancies, determine vaccine response, and perhaps has a role in autoimmune disease diagnostics [16–20]. We reported that repertoire sequencing is correlated with immune activity during rejection episodes in heart transplant recipients [21]. …”

Section: Introductionmentioning

confidence: 99%

B cell repertoires in HLA-sensitized kidney transplant candidates undergoing desensitization therapy

et al. 2017

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BackgroundKidney transplantation is the most effective treatment for end-stage renal disease. Sensitization refers to pre-existing antibodies against human leukocyte antigen (HLA) protein and remains a major barrier to successful transplantation. Despite implementation of desensitization strategies, many candidates fail to respond. Our objective was to determine whether measuring B cell repertoires could differentiate candidates that respond to desensitization therapy.MethodsWe developed an assay based on high-throughput DNA sequencing of the variable domain of the heavy chain of immunoglobulin genes to measure changes in B cell repertoires in 19 highly HLA-sensitized kidney transplant candidates undergoing desensitization and 7 controls with low to moderate HLA sensitization levels. Responders to desensitization had a decrease of 5% points or greater in cumulated calculated panel reactive antibody (cPRA) levels, and non-responders had no decrease in cPRA.ResultsDominant B cell clones were not observed in highly sensitized candidates, suggesting that the B cells responsible for sensitization are either not present in peripheral blood or present at comparable levels to other circulating B cells. Candidates that responded to desensitization therapy had pre-treatment repertoires composed of a larger fraction of class-switched (IgG and IgA) isotypes compared to non-responding candidates. After B cell depleting therapy, the proportion of switched isotypes increased and the mutation frequencies of the remaining non-switched isotypes (IgM and IgD) increased in both responders and non-responders, perhaps representing a shift in the repertoire towards memory B cells or plasmablasts. Conversely, after transplantation, non-switched isotypes with fewer mutations increased, suggesting a shift in the repertoire towards naïve B cells.ConclusionsRelative abundance of different B cell isotypes is strongly perturbed by desensitization therapy and transplantation, potentially reflecting changes in the relative abundance of memory and naïve B cell compartments. Candidates that responded to therapy experienced similar changes to those that did not respond. Further studies are required to understand differences between these two groups of highly sensitized kidney transplant candidates.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-017-1118-7) contains supplementary material, which is available to authorized users.

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Monitoring Pharmacologically Induced Immunosuppression by Immune Repertoire Sequencing to Detect Acute Allograft Rejection in Heart Transplant Patients: A Proof-of-Concept Diagnostic Accuracy Study

Cited by 22 publications

References 29 publications

Personalized treatment in heart transplantation

Personalized treatment in heart transplantation

Complete characterization of the human immune cell transcriptome using accurate full-length cDNA sequencing

B cell repertoires in HLA-sensitized kidney transplant candidates undergoing desensitization therapy

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