Faculty Bibliography

Memory B cells play an important role in immunity to pathogens as these cells are poised to rapidly differentiate into antibody-secreting cells upon antigen re-encounter. Memory B cells also develop over the course of HLA-sensitization during pregnancy and transplantation. In this review, we discuss the potential contribution of memory B cells to pregnancy sensitization as well as the impact of these cells on transplant candidacy and outcomes. We start by summarizing how B cell subsets are altered in pregnancy and discuss what is known about HLA-specific B cell responses given our current understanding of fetal antigen availability in maternal secondary lymphoid tissues. We then review the molecular mechanisms governing the generation and maintenance of memory B cells during infection - including the role of T follicular helper cells - and discuss the experimental evidence for the development of these cells during pregnancy. Finally, we discuss how memory B cells impact access to transplantation and transplant outcomes for a range of transplant recipients.

PURPOSE OF REVIEW/OBJECTIVE:Carbapenem-resistant Enterobacteriaceae (CRE) have emerged as a worldwide problem. Given their degree of immunosuppression and the level of contact with the healthcare system, solid organ transplant (SOT) recipients are at a disproportionately higher risk of acquisition, colonization, and infection with CRE, and outcomes from infection tend to be worse compared to non-transplant patients. Therapeutic options are limited for CRE infections although several newer agents have recently been approved for use. How well these agents perform in the setting of immunosuppression and SOT is unclear. We sought to review the epidemiology of CRE in SOT and the management principles. RECENT FINDINGS/RESULTS:CRE infections are becoming an increasing problem in SOT, and donor-derived infections present a challenge in the peri-transplant period. Newer treatments for CRE are emerging that are less toxic and potentially more effective than prior CRE-active agents, but supportive clinical data are limited. Newer beta-lactamase inhibitors have good activity against KPC carbapenemases, but they lack activity against metallo-beta-lactamases (e.g., NDM). Promising data is emerging with newer agents that have activity against most carbapenemases, but, again, clinical data is needed. Combination therapy in addition to optimal pharmacokinetic and pharmacodynamics may go some way to improve outcomes against these difficult-to-treat organisms. Other novel therapies that prevent the emergence of resistance (oral beta-lactamase inhibitors) and eradication of resistant Gram-negative colonization (fecal microbiota transplant) may eventually become part of a bundle approach to reduce CRE infections in the future. As in non-transplant patients, CRE infections in the transplant setting are challenging to treat and prevent. Infection prevention and control remains crucial to prevent widespread dissemination, and unique challenges exist with donor-derived CRE and how best to manage recipients in the peri-transplant period. Newer treatments are now in early-phase clinical studies, and in vitro activity data are supportive for several agents providing hope for improved outcomes with these typically difficult-to-treat and highly morbid infections in transplant recipients.

These updated guidelines from the Infectious Diseases Community of Practice of the American Society of Transplantation address vancomycin-resistant enterococci (VRE) infections in SOT candidates and recipients. VRE are an important cause of infection and have been named by the CDC as a serious public threat. Typically, a commensal of the gastrointestinal tract, VRE may become pathogenic after abdominal organ manipulation like transplantation. This guideline reviews the microbiology, antimicrobial resistance mechanisms, epidemiology, and clinical manifestations of VRE infection in the context of solid organ transplantation. Treatment regimens including combination therapies and novel investigational agents are also reviewed. Finally, an updated appraisal of infection control measures relevant to VRE infection and colonization is presented.

Although B cells expressing the IFNγR or the IFNγ-inducible transcription factor T-bet promote autoimmunity in Systemic Lupus Erythematosus (SLE)-prone mouse models, the role for IFNγ signaling in human antibody responses is unknown. We show that elevated levels of IFNγ in SLE patients correlate with expansion of the T-bet expressing IgD^negCD27^negCD11c⁺CXCR5^neg (DN2) pre-antibody secreting cell (pre-ASC) subset. We demonstrate that naïve B cells form T-bet^hi pre-ASCs following stimulation with either Th1 cells or with IFNγ, IL-2, anti-Ig and TLR7/8 ligand and that IL-21 dependent ASC formation is significantly enhanced by IFNγ or IFNγ-producing T cells. IFNγ promotes ASC development by synergizing with IL-2 and TLR7/8 ligands to induce genome-wide epigenetic reprogramming of B cells, which results in increased chromatin accessibility surrounding IRF4 and BLIMP1 binding motifs and epigenetic remodeling of IL21R and PRDM1 loci. Finally, we show that IFNγ signals poise B cells to differentiate by increasing their responsiveness to IL-21.

Graft-versus-host disease (GvHD) is a rare but fatal complication after solid organ transplantation arising in 1% to 2% of cases. We report 2 cases of GvHD after orthotopic liver transplantation. Both patients had a history of hepatitis C virus (HCV) infection prior to transplantation. Both cases presented between 1 and 4 months after transplantation with rash, pancytopenia, and/or diarrhea. Our second case also developed oral and ocular manifestations after liver transplantation, which are more commonly described after stem cell transplantation. Diagnosis in both cases was made by clinical presentation in conjunction with histopathology and flow cytometry. Both patients were treated by increasing immunosuppression with tacrolimus and high-dose steroids. Response to treatment differed based on the degree of pancytopenia. Our case report is distinguished by several factors such as the context of GvHD presentation and the role of HCV treatment. Diagnosis of GvHD is difficult and often delayed due to nonspecific presentation that overlaps with other conditions. Furthermore, the relation between HCV treatment and potential initiation of GvHD in solid organ transplant patients is unclear.

Post-transplantation infections are common in allograft recipients and should be expected in all immunocompromised hosts. Based on the need for immunosuppression in xenotransplantation, procedures developed to enhance safety in allotransplantation can be applied in future xenotransplantation clinical trials. Standardized approaches can be developed to guide the evaluation of common infectious syndromes in xenograft recipients. The opportunity created by screening of swine intended as xenograft donors has equal applicability to allotransplantation-notably broader screening strategies for allograft donors such as use of advanced sequencing modalities including broad-range molecular probes, microarrays, and high-throughput pyrosequencing. Considerations in management of allotransplant- and xenotransplant-associated infections are largely the same. Experience in xenotransplantation will continue to inform thinking regarding donor-derived infections in allotransplantation. We expect that experience in managing complex allotransplant recipients will similarly inform clinical trials in xenotransplantation.

Strongyloides stercoralis is a threadworm parasite with the unique capacity to complete its entire life cycle in a human host. Although asymptomatic in normal hosts, S stercoralis infection in solid organ transplant recipients is often severe, disseminated, and fatal. Risk factors for disease acquisition include travel to endemic regions. Antihelminth therapy should be instituted before transplantation for optimal clinical outcomes. Herein we review the epidemiology, biology, immune response, and diagnostic and screening strategies, as well as treatment modalities for S stercoralis in the solid organ transplant population.

PURPOSE OF REVIEW:Xenotransplantation offers a solution for the global shortage of available organs. However, cross-species transplantation and immunosuppression raises concerns about transmission of zoonotic infections to the recipient as well as to the public. RECENT FINDINGS:Here, we review the major infections of concern after xenotransplantation, risks of their transmission, diagnostic, therapeutic as well as prevention modalities for these infections after xenotransplantation. This review is particularly timely in light of recent advances in porcine genome editing technology that allow removal of retroviral sequences. SUMMARY:We cannot appreciate the full risk of infections after xenotransplantation in absence of clinical trials. However, there are guidelines for strict microbiologic monitoring and reporting, infectious diagnostic assay development, breeding and quarantine of graft source animals to limit infectious transmission.