Jonathan Merola

Non‐Alcoholic Fatty Liver Disease Following Liver Transplantation: A Clinical Review

Non‐alcoholic steatohepatitis (NASH) is rapidly becoming the leading indication for liver transplantation (LT) in the United States. While post‐transplantation outcomes are similar to other indications for transplant, recent evidence has suggested that reduction in risk factors for post‐transplant metabolic syndrome may impose a significant survival benefit in this patient population. Cardiovascular mortality is the leading cause of death following transplantation for NASH. While pre‐transplant pharmacologic and surgical approaches have been utilized to reduce cardiovascular risk factors following transplantation, the effectiveness of these treatment approaches in the post‐transplant setting is poorly defined. Studies are urgently needed in the treatment of this rapidly growing population.

A p190BRhoGAP mutation and prolonged RhoB activation in fatal systemic capillary leak syndrome

We describe a fatal case of pediatric systemic capillary leak (Clarkson’s disease) associated with a point mutation in p190BRhoGAP. Dermal microvascular endothelial cells (ECs) isolated from this patient form monolayers with similar levels and distribution of junctional proteins and transendothelial electrical resistance compared with normal human dermal microvascular ECs. However, patient-derived ECs demonstrate a greater increase in permeability and impaired recovery of barrier function in response to tumor necrosis factor (TNF) compared with normal donor EC cultures. TNF transiently activates RhoB in ECs coincident with developing leak, and inactivation of RhoB correlates with barrier recovery. The mutation in p190BRhoGAP impairs RhoB inactivation, and the mutant phenotype of patient-derived ECs is replicated by siRNA knockdown of p190BRhoGAP in normal ECs. These data suggest a previously unknown function for p190BRhoGAP in control of capillary EC barrier function that may also be important in acquired systemic capillary leak associated with critical illness in humans.

Recent advances in allograft vasculopathy.

Purpose of review Despite considerable advances in controlling acute rejection, the longevity of cardiac and renal allografts remains significantly limited by chronic rejection in the form of allograft vasculopathy. This review discusses recently reported mechanistic insights of allograft vasculopathy pathogenesis as well as recent clinical evaluations of new therapeutic approaches. Recent findings Although adaptive immunity is the major driver of allograft vasculopathy, natural killer cells mediate vasculopathic changes in a transplanted mouse heart following treatment with donor-specific antibody (DSA). However, natural killer cells may also dampen chronic inflammatory responses by killing donor-derived tissue-resident CD4+ T cells that provide help to host B cells, the source of DSA. DSA may directly contribute to vascular inflammation by inducing intracellular signaling cascades that upregulate leukocyte adhesion molecules, facilitating recruitment of neutrophils and monocytes. DSA-mediated complement activation additionally enhances endothelial alloimmunogenicity through activation of noncanonical NF-&kgr;B signaling. New clinical studies evaluating mammalian target of rapamycin and proteasome inhibitors to target these pathways have been reported. Summary Allograft vasculopathy is a disorder resulting from several innate and adaptive alloimmune responses. Mechanistic insights from preclinical studies have identified agents that are currently being investigated in clinical trials.

Antigen Presentation by Vascular Cells

Antigen presentation by cells of the vessel wall may initiate rapid and localized memory immune responses in peripheral tissues. Peptide antigens displayed on major histocompatibility complex (MHC) molecules on the surface of endothelial cells (ECs) can be recognized by T cell receptors on circulating effector memory T cells (TEM), triggering both transendothelial migration and activation. The array of co-stimulatory receptors, adhesion molecules, and cytokines expressed by ECs serves to modulate T cell activation responses. While the effects of these interactions vary among species, vascular beds, and vascular segments within the same tissue, they are capable of triggering allograft rejection without direct involvement of professional antigen-presenting cells and may play a similar role in host defense against infections and in autoimmunity. Once across the endothelium, extravasating TEM then contact mural cells of the vessel wall, including pericytes or vascular smooth muscle cells, which may also present antigens and provide signals that further regulate T cell responses. Collectively, these interactions provide an unexplored opportunity in which targeting of vascular cells can be used to modulate immune responses. In organ transplantation, targeting ECs with siRNA to reduce expression of MHC molecules may additionally mitigate perioperative injuries by preformed alloantibodies, further reducing the risk of graft rejection. Similarly, genetic manipulation of vascular cells to minimize antigen-dependent responses can be used to increase perfusion of tissue engineered organs without triggering rejection.

Successful treatment of primary donor-derived human herpesvirus-8 infection and hepatic Kaposi Sarcoma in an adult liver transplant recipient

Kaposi sarcoma (KS) may rarely occur in transplant recipients through primary human herpesvirus‐8 (HHV‐8) infection from a seropositive donor. This report describes a patient who developed hepatic KS after receiving a split liver transplant from an HHV‐8‐positive donor. The recipient was treated with liposomal doxorubicin after reduction in immunosuppression led to acute cellular rejection. This treatment achieved regression of KS while preserving allograft function, demonstrating a successful therapeutic strategy for this malignancy.

Interferon- γ converts human microvascular pericytes into negative regulators of alloimmunity through induction of indoleamine 2,3-dioxygenase 1

Early acute rejection of human allografts is mediated by circulating alloreactive host effector memory T cells (TEM). TEM infiltration typically occurs across graft postcapillary venules and involves sequential interactions with graft-derived endothelial cells (ECs) and pericytes (PCs). While the role of ECs in allograft rejection has been extensively studied, contributions of PCs to this process are largely unknown. This study aimed to characterize the effects and mechanisms of interactions between human PCs and allogeneic TEM. We report that unstimulated PCs, like ECs, can directly present alloantigen to TEM, but while IFN-γ-activated ECs (γ-ECs) show increased ability to stimulate alloreactive T cells, IFN-γ-activated PCs (γ-PCs) instead suppress TEM proliferation but not cytokine production or signaling. RNA sequencing analysis of PCs, γ-PCs, ECs, and γ-ECs reveal induction of indoleamine 2,3-dioxygenase 1 (IDO1) in γ-PCs to significantly higher levels than in γ-ECs that correlates with tryptophan depletion in vitro. Consistently, shRNA knockdown of IDO1 markedly reduces γ-PC-mediated immunoregulatory effects. Furthermore, human PCs express IDO1 in a skin allograft rejection humanized mouse model and in human renal allografts with acute T cell-mediated rejection. We conclude that immunosuppressive properties of human PCs are not intrinsic but instead result from IFN-γ-induced IDO1-mediated tryptophan depletion.

Allograft transmission of hepatitis C during the window period: Weighing the new risks and costs in the era of donor shortage

Organ shortages have necessitated utilization of allografts from Public Health Service (PHS) increased risk deceased donors. Such organs are gifted by donors with proximate social risk factors for transmission of viral hepatitis and human immunodeficiency virus (HIV).1 Such allografts are increasingly available with the current opioid epidemic, often from firsttime and naïve opiate users who are otherwise healthy, enhancing transmission risk and diminishing the sensitivity of pretransplant viral screening.2 A “window period” in which antibodies to hepatitis C (HCV) remain undetectable for several weeks following initial exposure affords an interval in which infection may elude screening serology. Two patients recently contracted “window period” infections at our center, posing implications for informed consent of potential recipients as well as treatment coverage by thirdparty payers (Table 1).