Effect of mTORC1/mTORC2 inhibition on T cell function: potential role in graft‐versus‐host disease control

The mechanistic target of rapamycin (mTOR) pathway is crucial for the activation and function of T cells, which play an essential role in the development of graft‐versus‐host disease (GvHD). Despite its partial ability to block mTOR pathway, the mTORC1 inhibitor rapamycin has shown encouraging results in the control of GvHD. Therefore, we considered that simultaneous targeting of both mTORC1 and mTORC2 complexes could exert a more potent inhibition of T cell activation and, thus, could have utility in GvHD control. To assess this assumption, we have used the dual mTORC1/mTORC2 inhibitors CC214‐1 and CC214‐2. In vitro studies confirmed the superior ability of CC214‐1 versus rapamycin to block mTORC1 and mTORC2 activity and to reduce T cell proliferation. Both drugs induced a similar decrease in Th1/Th2 cytokine secretion, but CC214‐1 was more efficient in inhibiting naïve T cell activation and the expression of T‐cell activation markers. In addition, CC214‐1 induced specific tolerance against alloantigens, while preserving anti‐cytomegalovirus response. Finally, in a mouse model of GvHD, the administration of CC214‐2 significantly improved mice survival and decreased GvHD‐induced damages. In conclusion, the current study shows, for the first time, the immunosuppressive ability of CC214‐1 on T lymphocytes and illustrates the role of CC214‐2 in the allogeneic transplantation setting as a possible GvHD prophylaxis agent.     

Pathogenesis of acute graft‐versus‐host disease: from intestinal microbiota alterations to donor T cell activation

Acute graft‐versus‐host disease (aGVHD) is a major life‐threatening complication of allogeneic haematopoietic cell transplantation (allo‐HCT). Here we discuss the aGVHD pathophysiology initiated by multiple signals that cause alloreactive T‐cell activation. The outcome of such donor T‐cell activation is influenced by T‐cell receptor‐signal strength, anatomical location, co‐stimulatory/co‐inhibitory signals and differentiation stage (naive, effector/memory) of T‐cells. Additionally, cross‐priming of T cells to antigens expressed by pathogens can contribute to aGVHD‐mediated tissue injury. In addition to the properties of donor T‐cell activation, highly specialized tissue resident cell types, such as innate lymphoid cells, antigen‐presenting cells, immune regulatory cells and various intestinal cell populations are critically involved in aGVHD pathogenesis. The role of the thymus and secondary lymphoid tissue injury, non‐haematopoietic cells, intestinal microflora, cytokines, chemokines, microRNAs, metabolites and kinases in aGVHD pathophysiology will be highlighted. Acute GVHD pathogenic mechanisms will be connected to novel therapeutic approaches under development for, and tested in, the clinic.     

Dermatopathic lymphadenopathy with Langerhans cell chimerism in graft‐versus‐host disease of the skin

Dermatopathic lymphadenopathy (DL) is well‐known in inflammatory skin disease; however, it has not been reported in graft‐versus‐host disease (GvHD) after allogeneic stem cell transplantation. Here, we report 2 cases of DL in patients with acute GvHD of the skin and demonstrate complete donor chimerism of Langerhans cells within the lymph nodes.     

Prevention of acute graft‐versus‐host disease by humanized anti‐CD26 monoclonal antibody

CD26 (DPP4) is a T cell costimulatory molecule as well as T cell activation marker, and CD26⁺ T cells are accumulated in inflamed tissues, such as rheumatoid synovitis and autoimmune thyroiditis. In the present study, we found accumulation of CD26⁺ T cells in graft‐versus‐host disease (GVHD) target organs. To expand our in vitro findings to an in vivo system, we examined CD26‐dependent organ injury in a xenogeneic GVHD (x‐GVHD) murine model. Following intraperitoneal injection of human peripheral blood mononuclear cells into non‐obese diabetic severe combined immunodeficiency/γ_c^?/? mice (hu‐PBL‐NOG mice), the mice exhibited the onset of GVHD symptoms associated with the presence of CD26^high human lymphocytes in the peripheral blood and GVHD target tissues. Administration of humanized anti‐human CD26 monoclonal antibody (mAb) decreased x‐GVHD severity and prolonged survival in hu‐PBL‐NOG mice without loss of engraftment of human T cells, while increasing doses of CTLA4‐ immunoglobulin fusion protein diminished engraftment of human lymphocytes. Importantly, anti‐CD26 mAb treatment preserved the graft‐versus‐leukaemia effects in studies using cotransplantation of P815 murine leukaemic cells. In addition, CD26⁺ lymphocytes infiltrated the GVHD patients' target tissues. Altogether, our data indicate a role for CD26 in the regulation of GVHD and point to CD26 as a novel target for therapeutic intervention in this disease.     

Invasive zygomycosis in patients with graft‐versus‐host disease after allogeneic stem cell transplantation

M. Leithauser, C. Kahl, C. Aepinus, F. Prall, M. Maruschke, H. Riemer, D. Wolff, K. Jost, I. Hilgendorf, M. Freund, C. Junghanss. Invasive zygomycosis in patients with graft‐versus‐host disease after allogeneic stem cell transplantation
Transpl Infect Dis 2010: 12: 251–257. All rights reserved Abstract: Invasive mold infections are a threat to immunosuppressed patients such as patients with graft‐versus‐host disease (GVHD) after allogeneic stem cell transplantation (SCT). Up to 10% of SCT recipients develop invasive aspergillosis (IA). Invasive zygomycosis (IZ) may occur during treatment against IA. Here we report 4 SCT patients with GVHD diagnosed with IZ. All patients had received myeloablative hematopoietic SCT and developed chronic GVHD requiring systemic immunosuppression. Underlying diseases were acute lymphocytic leukemia (2), osteomyelofibrosis, and multiple myeloma. All patients had developed pulmonary infiltration that led to initiation of antifungal therapy. Treatment for IA was voriconazole, caspofungin, or itraconazole. Organs involved with zygomycosis were lung, nasal sinus, skin, and kidney. Treatment with liposomal amphotericin and posaconazole was initiated in all patients, and 2 patients also had surgical debridement as well. Despite intensive treatment, no patient survived. IZ is becoming more common in patients with GVHD on successful treatment for IA. Even non‐specific symptoms are suspicious in this group of patients and need to be evaluated by vigorous diagnostics. Despite effective antifungals and surgical intervention, the prognosis is grim in patients with active GVHD, as immunoreconstitution is mandatory for successful management.     

Nephrotic syndrome as a complication of chronic graft‐versus‐host disease after allogeneic haemopoietic stem cell transplantation

Nephrotic syndrome (NS) is a rare complication following allogeneic haemopoietic stem cell transplantation (allo‐HSCT), with limited current understanding of its pathogenesis. Here, we describe four cases of NS following allo‐HSCT diagnosed at our institutions to identify key clinical and pathological features. In addition, a PubMed search was performed to identify existing reports that were pooled together with our cases for analysis. NS occurred as a late complication following allo‐HSCT, with median onset 19.5 months after transplant (range: 3.9–84 months). The most common histopathology observed was membranous nephropathy; however, cases of minimal change disease have also been reported. There is a high incidence of prior extra‐renal graft‐versus‐host disease (GvHD), with all four of our cases and 82% of published cases having prior GvHD. Glucocorticosteroids are the most common treatment, with variable degrees of response. Responses to immunosuppression with calcineurin inhibitors and rituximab have been described in steroid‐refractory cases.     

Optimal management of chronic graft‐versus‐host disease in children

Chronic graft‐versus‐host disease (GVHD) is a major complication after allogeneic haematopoietic stem cell transplantation (HSCT). Not only is it the major cause of late mortality in HSCT patients, but it also accounts for significant morbidity. Much of the literature on chronic GVHD has focused on adults. Chronic GVHD is of major importance in children, especially since they have years to live following the complications of chronic GVHD and its therapy. The goal is to review incidence, manifestations, and therapies, especially when applicable to the paediatric population.     

Demodicidosis simulating acute graft‐versus‐host disease after allogeneic stem cell transplantation in one patient with acute lymphoblastic leukemia

One important differential diagnosis of facial erythema in a patient receiving an allogeneic bone marrow transplant (BMT) is acute graft‐versus‐host disease (GVHD). Demodex folliculorum has been rarely implicated in the development of facial rashes in immunosuppressed patients, including BMT recipients. We report the case of a patient, suffering from acute lymphoblastic leukemia, who after bone marrow transplantation developed a facial rash due to D. folliculorum mimicking GVHD. Differential diagnosis of facial rashes and demodicidosis after BMT is reviewed.     

Human papillomavirus reactivation following treatment of genital graft‐versus‐host disease

Vaginal chronic graft‐versus‐host disease (cGVHD) is a common complication of stem cell transplantation. Human papillomavirus (HPV) disease can reactivate after transplantation, presumably because of immune factors affecting systemic immunity, such as waning antibody titers, impaired T‐ and B‐lymphocyte responses, and the use of immunosuppressive therapies. However, a relationship between the use of local immunosuppressive agents and HPV reactivation and spread has not been previously described, to our knowledge. A 30‐year‐old woman, 2 years post transplant receiving systemic cyclosporine for cGVHD, was treated with vaginal dilators, topical corticosteroids, and estrogen for vaginal cGVHD. Colposcopy and biopsy for abnormal cytology revealed condylomatous cervicitis. Over the next 4 months, while continuing dilator therapy, linear verrucous lesions developed in the vagina and vulva, and were successfully treated with laser therapy. Use of local immunosuppression and dilators for genital GVHD can enhance spread of HPV infection. Integration of HPV screening and treatment into the care of women with genital cGVHD and development of strategies to manage both conditions simultaneously are warranted.     

Oral chronic graft‐versus‐host disease in Australia: clinical features and challenges in management

Data from the Australasian Bone Marrow Transplant Recipient Registry show a steady increase in the number of allogeneic haemopoietic stem cell transplantations (HSCT) performed annually in Australia and New Zealand. In 2012, 629 allogeneic HSCT were performed. Allogeneic HSCT is associated with numerous potential complications, including chronic graft‐versus‐host disease (cGVHD). The oral cavity is one of the most frequent sites affected by cGvHD, often leading to significant disability and reduced quality of life. Management strategies are often complex, of variable efficacy and influenced by the availability of various therapeutic agents, access to compounding pharmacies and associated costs. This paper summarises the current status of allogeneic HSCT in Australia and New Zealand with a focus on oral cGvHD and the associated challenges in its management.     

The initial phase of graft‐versus‐host disease is associated with a decrease of CD4+CD25+ regulatory T cells in the peripheral blood of patients after allogeneic stem cell transplantation

The mechanisms that induce and control the alloimmune inflammation of graft‐versus‐host disease (GvHD) after allogeneic stem cell transplantation (allo‐SCT) are still incompletely understood. In the murine system, GvHD can be suppressed by CD4⁺CD25⁺ regulatory T cells (TREG), which are generally involved in the suppression of inflammatory reactions. A disruption of the homeostasis between TREG and conventional T cells might therefore be associated with the inflammatory reactions of GvHD. We repetitively measured the frequency of TREG in the peripheral blood of 29 patients within the first 71–373 days after allo‐SCT and correlated the results with the clinical course. We demonstrate that the initial phase of GvHD is associated with a significant reduction of TREG in the peripheral blood, while at later stages and during intensified immunosuppressive therapy, increased numbers of TREG appear. These results might indicate a pathogenic role for reduced numbers of TREG in the induction of human GvHD.     

Acanthamoeba infection in a patient with chronic graft‐versus‐host disease occurring during treatment with voriconazole

Abstract: We report a case of disseminated infection with Acanthamoeba in a patient with graft‐versus‐host disease after hematopoietic stem cell transplant (HSCT) for acute lymphocytic leukemia. The infection involved the brain, skin, and lungs and occurred despite treatment with voriconazole for mold prophylaxis, and did not respond to treatment with multiple other agents reported to have activity against Acanthamoeba. To our knowledge, infection with Acanthamoeba has been reported in 4 other patients after HSCT or bone marrow transplant, and our case is the first to be diagnosed ante‐mortem.