James Mathew

Northwestern University | NU · Comprehensive Transplant Center

Introduction Donor hematopoietic stem cell (DHSC) infusions are increasingly being studied in transplant patients for tolerance induction. Methods To analyze the fate of infused DHSCs in patients, we developed an in vitro culture system utilizing CD34⁺DHSCs stimulated with irradiated allogeneic cells in cytokine supplemented medium long-term. Res...

Despite the advances in therapeutic interventions, solid organ transplantation (SOT) remains the “gold standard” treatment for patients with end-stage organ failure. Recently, vascularized composite allotransplantation (VCA) has reemerged as a feasible treatment option for patients with complex composite tissue defects. In both SOT and VCA, ischemi...

Background: Thirty-seven patients have received a living-donor kidney transplant in a phase 2 study designed to induce tolerance with facilitated allogeneic hematopoietic stem cell transplant. The study protocol is based on tolerogenic CD8+/T-cell receptor- facilitating cells (FCR001; also including hematopoietic stem cells and αβ-T-cell receptor+...

Regulatory T cells (Tregs) are critical for tolerance in humans. The exact mechanisms by which the loss of peripheral tolerance leads to the development of autoimmunity and the specific role Tregs play in allograft tolerance are not fully understood; however, this population of T cells presents a unique opportunity in the development of targeted th...

Recipients of solid organ transplantation (SOT) rely on life-long immunosuppression (IS), which is associated with significant side effects. Extracorporeal photochemotherapy (ECP) is a safe, existing cellular therapy used to treat transplant rejection by modulating the recipient’s own blood cells. We sought to induce donor-specific hypo-responsiven...

Recipients of solid organ transplantation (SOT) rely on life-long immunosuppression (IS), which is associated with significant side effects. Extracorporeal photochemotherapy (ECP) is a safe, existing cellular therapy used to treat transplant rejection by modulating the recipient’s own blood cells. We sought to induce donor-specific hypo-responsiven...

Despite advances in post-transplant management, the long-term survival rate of kidney grafts and patients has not improved as approximately forty percent of transplants fails within ten years after transplantation. Both immunologic and non-immunologic factors contribute to late allograft loss. Chronic kidney transplant rejection (CKTR) is often cli...

Early elimination of tacrolimus in favor of everolimus can improve renal function in liver transplant recipients. However, as this approach increases the risk of acute rejection, it may benefit from predictive biomarkers guiding weaning. We enrolled 20 recipients on stable tacrolimus + everolimus to undergo tacrolimus withdrawal early post-liver tr...

Purpose of review: Immunological factors are a major cause of kidney allograft loss. Calcineurin inhibitors (CNIs) have improved short-term kidney allograft survival; however, they in turn contribute to long-term kidney allograft loss from chronic CNI nephrotoxicity. Tolerance induction in transplantation can avoid the long-term adverse effects of...

Long-term immunosuppression in transplant recipients is associated with important adverse effects including increased risk of infection and malignancy. New data from the ONE Study suggests that use of cell-based medicinal products containing regulatory immune cells is a potentially useful therapeutic strategy to enable minimization of immunosuppres...

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

In 2017, the American Society of Transplantation launched the Outstanding Questions in Transplantation Research forum to stimulate a community‐wide discussion of how the field is evolving and to help identify areas where a better dialogue between clinicians and researchers could result in great advancements. Tolerance emerged as a topic of great in...

Background and aims: As conversion from calcineurin inhibitor to sirolimus (SRL), a mechanistic target of rapamycin inhibitor (mTOR-I), has been shown to enhance immunoregulatory profiles in liver transplant (LT) recipients (LTRs), mTOR-I therapy might allow for increased success of immunosuppression (IS) withdrawal. Our aim was to determine if op...

The three-dimensional organization of the genome in mammalian interphase nuclei is intrinsically linked to the regulation of gene expression. Whole chromosome territories and their encoded gene loci occupy preferential positions within the nucleus that changes according to the expression profile of a given cell lineage or stage. To further illumina...

Calcineurin inhibitors (CNI), the cornerstone of immunosuppression after transplantation are implicated in nephrotoxicity and allograft dysfunction. We hypothesized that combined low doses of CNI and Everolimus (EVR) may result in better graft outcomes and greater tolerogenic milieu. Forty adult renal transplant recipients were prospectively random...

The prospect of eliminating the long term costs and side effects of drug-based immunosuppression (IS) is a compelling reason to pursue the establishment of transplant tolerance. Tolerance in kidney transplant (KTx) recipients has been achieved through the infusion of donor HSC under some form of conditioning. The increased upfront cost and intensiv...

There is considerable interest in therapeutic transfer of regulatory T cells (Tregs) for controlling aberrant immune responses. Initial clinical trials have shown the safety of Tregs in hematopoietic stem cell transplant recipients and subjects with juvenile diabetes. Our hypothesis is that infusion(s) of Tregs may induce transplant tolerance thus...

Immunosuppression after solid organ transplantation is a delicate balance of the immune response and is a complex phenomenon with many factors involved. Despite advances in the care of patients receiving organ transplants the adverse effects associated with immunosuppressive agents and the risks of long-term immunosuppression present a series of ch...

Kidney transplant recipients given donor hematopoietic stem cells from their HLA-identical living related donors have now been followed between 5 and 9 ½ years post-operatively. Recipients who were designated as tolerant (Tol) have remained so since the last report when the 5 year (biopsy associated) milestone was reached. There has been 1 mortalit...

Development of tolerance protocols requires assays or biomarkers that distinguish tolerant recipients from non-tolerant ones to be established. In addition, a thorough understanding of the plausible mechanisms associated with clinical transplant tolerance is necessary to take the field forward. Unlike the majority of molecular signature analyses ut...

Donor-specific CD4+CD127-CD25+FOXP3+ regulatory T cells (AgTregs) have the potential to induce clinical transplant tolerance; however, their expansion ex vivo remains challenging. We optimized a novel expansion protocol to stimulate donor-specific Tregs using soluble 4-trimer CD40 ligand (CD40L)-activated donor B cells that expressed mature antigen...

The modern immunosuppression regimen has greatly improved short-term allograft outcomes but not long-term allograft survival. Complications associated with immunosuppression, specifically nephrotoxicity and infection risk, significantly affect graft and patient survival. Inducing and understanding pathways underlying clinical tolerance after transp...

Aim CD4+CD127−CD25+FOXP3+ Regulatory T cells (Tregs) are shown to be enhanced in tolerant transplant patients and after ex vivo expansion to prolong graft survival in animal models without immunosuppression. Therefore, a number of centers have initiated clinical trials with expanded Tregs. The purpose of the present study was to further optimize th...

36 subjects have been enrolled and 31 transplanted in a phase 2 protocol (IDE 13947) to induce tolerance in recipients of living donor renal allografts (KTx). The protocol is based upon tolerogenic CD8+/TCR-facilitating cells (FCRx) and 200 cGy TBI-based nonmyeloablative conditioning. Recipients received fludarabine (30mg/kg/dose, days -5,-4,-3), c...

Everolimus (EVL) is a novel mTOR-inhibitor similar to sirolimus (SRL) that is used in organ transplant recipients, often in combination with tacrolimus (TAC) or mycophenolate (MPA). The current study aims to determine its effects on regulatory T cells. Increasing concentrations of EVL, MPA and TAC alone or in combination were added to MLRs of healt...

Historically, hepatitis B virus (HBV) liver transplantation (LT) recipients have less acute cellular rejection (ACR) than those without HBV. We questioned whether this has persisted in an era of decreased Hepatitis B immunoglobulin use (HBIG) given its in vitro immunoregulatory effects. We compared the incidence, risk factors and outcomes of ACR am...

We previously described early results of a nonchimeric operational tolerance protocol in human leukocyte antigen (HLA)-identical living donor renal transplants and now update these results. Recipients given alemtuzumab, tacrolimus/MPA with early sirolimus conversion were multiply infused with donor hematopoietic CD34(+) stem cells. Immunosuppressio...

The direct effect of immunosuppressive drugs calcineurin inhibitor (Tacrolimus, TAC) and mTOR inhibitor (Sirolimus, SRL) on B cell activation, differentiation and proliferation is not well documented. Purified human B cells from healthy volunteers were stimulated through the B Cell Receptor with Anti-IgM + anti-CD40 + IL21 in the absence / presence...

Previously, we had reported the role of tacrolimus (TAC) versus sirolimus (SRL) on the generation of regulatory T cells (Tregs) in primary MLR assays with SRL, demonstrating a uniquely supportive effect. However, the mechanisms associated with their actions on alloreactive human are not fully understood. Therefore, we tested whether TAC and SRL dif...

Nineteen subjects have more than 18 months follow-up in a phase IIb tolerance protocol in HLA-mismatched recipients of living donor kidney plus facilitating cell enriched hematopoietic stem cell allografts (FCRx). Reduced intensity conditioning preceded a kidney allograft, followed the next day by FCRx. Twelve have achieved stable donor chimerism a...

Long-term outcomes of intestinal transplantation are limited by infection and rejection. To understand the underlying immune mechanisms, graft infiltrating and peripheral blood cells were analyzed using multiple ex vivo assays in intestinal transplantation recipients. Infiltrating cells from rejected (graft enterectomy for rejection) and accepted o...

Solid organ transplant recipients generally require life-long immunosuppressive agents to maintain graft acceptance. This is associated with a number of toxicities, including renal dysfunction, metabolic abnormalities, opportunistic infection and malignancies. Calcineurin inhibitors, the most frequently used agents for immunosuppression, induce nep...

The cellular immune response is the most important mediator of allograft rejection and is a major barrier to transplant tolerance. Delineation of the depth and breadth of the alloreactive T cell repertoire and subsequent application of the technology to the clinic may improve patient outcomes. As a first step toward this, we have used MLR and high-...

Tacrolimus and sirolimus are commonly used maintenance immunosuppressants in kidney transplantation. As their effects on immune cells and allograft molecular profiles have not been elucidated, we characterized the effects of tacrolimus to sirolimus conversion on the frequency and function of T cells, and on graft molecular profiles. Samples from re...

A phase 2 protocol was developed to attempt to induce donor-specific tolerance to renal allografts in related and unrelated donor/recipient combinations (IND 13947 phase 2). Subjects were conditioned with fludarabine (days -5, -4, -3), cyclophosphamide (50 mg/ky days -3 and +3), and 200 cGy total body irradiation. The kidney transplant was performe...

Aim Stable chimerism and tolerance can be achieved in HLA-disparate kidney recipients treated with donor hematopoietic stem cell (DHCS) transplantation supplemented with facilitating cells (FC) derived from mobilized peripheral blood (mPB) after living donor leukopheresis (Sci. Transl. Med. 2012; 4 (124): 124re28). The use of deceased donor (dd) ve...

Aim In an HLA Identical (HLA-id) renal transplant (RT) tolerance trial using donor hematopoietic stem cells, alemtuzumab induction, and temporary maintenance immunosuppression (IS), primarily with sirolimus, 6 of the first 12 recipients achieved non-chimeric tolerance (IS-free for over 1 year without rejection in biopsies at >3 years post-op). We a...

Aim In recent publication we reported that durable chimerism and tolerance can be achieved with minimal toxicity and without GVHD in highly-mismatched transplant (Tx) recipients through low intensity conditioning and a living donor kidney Tx with a dose of hematopoietic stem cells (HSC) enriched for facilitating cells (FC) (Sci. Transl. Med. 2012;...

It is unclear if new costimulatory blockade agents, such as the cytotoxic T lymphocyte-associated antigen 4-Ig molecule belatacept (BEL), promote or inhibit the potential for immunologic tolerance in transplantation. We therefore tested the in vitro effects of BEL on human regulatory T cells (Tregs) in mixed lymphocyte reactions (MLR) alone and in...

The ability to achieve immunologic tolerance after transplantation is a therapeutic goal. Here, we report interim results from an ongoing trial of tolerance in HLA-identical sibling renal transplantation. The immunosuppressive regimen included alemtuzumab induction, donor hematopoietic stem cells, tacrolimus/mycophenolate immunosuppression converte...

Unlabelled: Immunosuppression (IS) withdrawal from calcineurin inhibitors is only possible in ≈ 20% of liver transplant recipients. However, mammalian target of rapamycin inhibitors (e.g., sirolimus; SRL) appear to be more immunoregulatory and might promote a tolerant state for withdrawal. Our aim was to determine whether systemic (i.e., blood, ma...

In this chapter, we describe studies on non-chimeric human leukocyte antigen (HLA) identical tolerance and chimeric HLA disparate tolerance brought about by infusions of hematopoietic stem cells from the renal donor (DHSC). In our HLA identical series, 4 DHSC infusions were administered during the first 9 months posttransplant in a highly immunoreg...

Aim Belatacept (BLT) has recently been approved in renal transplantation so as to avoid side effects of CNI. However, the effect of BLT alone or in combination with other maintenance agents on regulatory T cells is not clear. Methods We tested BLT and Mycophenolic Acid (MPA; active form of Cellcept or Myfortic being used clinically together with B...

Ekong UD, Mathew J, Melin-Aldana H, Wang D, Alonso EM. Successful resolution of inflammation and increased regulatory T cells in sirolimus-treated post-transplant allograft hepatitis. Pediatr Transplantation 2012: 16: 165–175. © 2012 John Wiley & Sons A/S. Abstract: This retrospective case series reviews our center’s experience with sirolimus and a...

Human CD8(+) regulatory T cells, particularly the CD8(+)CD28(-) T suppressor cells, have emerged as an important modulator of alloimmunity. Understanding the conditions under which these cells are induced and/or expanded would greatly facilitate their application in future clinical trials. In the current study, we develop a novel strategy that comb...

We studied the effects of alemtuzumab on T-regulatory cells (Tregs) during alloactivation, first by differences in depletion of various naive versus alloactivated cell subsets in peripheral blood of healthy volunteers, then by adding serial concentrations to human leukocyte antigen (HLA)-DR-matched and -mismatched responding and stimulating cells i...

Assessment of cell-cell contact requirement for CTL inhibitory activity by MLR-Tregs in the micro-CML*. (DOC)

Although immunoregulation of alloreactive human CTLs has been described, the direct influence of CD4(+) Tregs on CD8(+) cytotoxicity and the interactive mechanisms have not been well clarified. Therefore, human CD4(+)CD127(-)CD25(+)FOXP3(+) Tregs were generated in MLR, immunoselected and their allospecific regulatory functions and associated mechan...

Infusions of bone marrow-derived cells together with 'space making' continue to be tested in clinical organ transplant tolerance protocols. These trials are based on the hypothesis that this might produce initial multilineage chimerism. There is some evidence that this in turn induces regulatory cells that control alloimmunity. Although a wealth of...

Tacrolimus (TAC) and sirolimus (SRL), two commonly used immunosuppressive agents, have demonstrated contrasting immunoregulatory effects. We recently described factors affecting the generation of allospecific CD4CD25 forkhead/winged helix transcription factor P3 (FOXP3) T-regulatory (Treg) cells in mixed lymphocyte reaction (Treg MLR) and now repor...

Ischemia-reperfusion (IR) injury is an important cause of primary graft failure in lung transplantation. In this study, viral interleukin-10 (vIL-10)-engineered mesenchymal stem cells (MSCs) were tested for their ability to prevent lung IR injury. Bone marrow-derived MSCs were transduced with rvIL-10-retrovirus. After 120 min of warm left lung isch...

Ex vivo identification of donor-specific unresponsiveness in organ transplant recipients is important for immunosuppression (IS) minimization. We tested three groups of stable living, related-donor kidney transplant patients up to 11 years postoperatively, i.e., 20 haploidenticals with donor bone marrow cell (DBMC) infusions, eight noninfused haplo...

Controversy exists about the conditions effecting the development of forkhead/winghead helix transcription factor P3 (FOXP3) expressing T cells and their relevance in transplant recipients. We generated carboxy-fluorescein diacetate succinimidyl ester-labeled CD4+CD25 high FOXP3+ cells in mixed lymphocyte reactions (MLRs) ("the Treg MLR"), with var...

Ischemia-reperfusion injury (IR) is an important cause for lung graft loss (~30%). In this study, MSC & viral interleukin-10 (vIL-10) engineered MSC were tested for their ability to prevent lung IR injury. Bone marrow derived MSC from Lewis rat were transduced with rvIL-10-retrovirus & selected on neomycin. Following 120 min of left lung ischemia i...

We compared peripheral blood immunophenotyping in 31 adult liver transplant recipients on differing long-term immunosuppressive (IS) monotherapy with and without peri-transplantation alemtuzumab (AL) induction. All patients had been stable on monotherapy with either sirolimus (SRL) (n = 10) or without SRL (tacrolimus (TAC) (n = 10), mycophenolate m...

The immunoregulatory role of human donor bone marrow cells (DBMC) has been studied extensively in our laboratory using in vitro and ex vivo assays. However, new experimental systems that can overcome the limitations of tissue culture assays but with more clinical relevance than purely animal experimentation, needed to be generated. Therefore we hav...

Ischemic heart disease, especially myocardial infarction, is an important cause of heart failure. However, therapeutic potential of mesenchymal stem cells (MSC) for myocardial or pulmonary ischemia reperfusion (IR) injury is not well studied. Interleukin-10 (IL-10) is an anti-inflammatory cytokine. In this study MSC and IL-10 engineered MSC were te...

We examined the in vitro inhibition of human monocyte-derived dendritic cells (DC) maturation via NF-kappaB blockade on T-cell allostimulation, cytokine production, and regulatory T-cell generation. DC were generated from CD14+ monocytes isolated from peripheral blood using GM-CSF and IL-4 for differentiation and TNF-alpha, IL-1beta, and PGE2 as ma...

To describe the effect of the splenic allograft in human multivisceral transplantation. We performed transplants of the spleen as part of a multivisceral graft in an attempt to decrease both the risk of infection from an asplenic state and the risk of rejection by a possible tolerogenic effect. To our knowledge, this is the first report of human sp...