Transient Lymphopenia Breaks Costimulatory Blockade‐Based Peripheral Tolerance and Initiates Cardiac Allograft Rejection

Lymphopenia is induced by lymphoablative therapies and chronic viral infections. We assessed the impact of lymphopenia on cardiac allograft survival in recipients conditioned with peritransplant costimulatory blockade (CB) to promote long‐term graft acceptance. After vascularized MHC‐mismatched heterotopic heart grafts were stably accepted through CB, lymphopenia was induced on day 60 posttransplant by 6.5 Gy irradiation or by administration of anti‐CD4 plus anti‐CD8 mAb. Long‐term surviving allografts were gradually rejected after lymphodepletion (MST = 74 ± 5 days postirradiation). Histological analyses indicated signs of severe rejection in allografts following lymphodepletion, including mononuclear cell infiltration and obliterative vasculopathy. Lymphodepletion of CB conditioned recipients induced increases in CD44^high effector/memory T cells in lymphatic organs and strong recovery of donor‐reactive T cell responses, indicating lymphopenia‐induced proliferation (LIP) and donor alloimmune responses occurring in the host. T regulatory (CD4⁺ Foxp³⁺) cell and B cell numbers as well as donor‐specific antibody titers also increased during allograft rejection in CB conditioned recipients given lymphodepletion. These observations suggest that allograft rejection following partial lymphocyte depletion is mediated by LIP of donor‐reactive memory T cells. As lymphopenia may cause unexpected rejection of stable allografts, adequate strategies must be developed to control T cell proliferation and differentiation during lymphopenia.     

Antibody deficiency associated with an inherited autosomal dominant mutation in TWEAK

Mutations in the TNF family of proteins have been associated with inherited forms of immune deficiency. Using an array-based sequencing assay, we identified an autosomal-dominant deficiency in TNF-like weak inducer of apoptosis (TWEAK; TNFSF12) in a kindred with recurrent infection and impaired antibody responses to protein and polysaccharide vaccines. This mutation occurs in the sixth exon of TWEAK and results in the amino acid substitution R145C within the conserved TNF-homology domain of the full-length protein. TWEAK mutant protein formed high molecular weight aggregates under nonreducing conditions, suggesting an increased propensity for intermolecular interactions. As a result, mutant TWEAK associated with B-cell–activating factor (BAFF) protein and down-regulated the BAFF-mediated activation of the noncanonical NF-κB pathway through inhibition of p100 processing to p52, resulting in inhibition of BAFF-dependent B-cell survival and proliferation. As BAFF mediates T-cell–independent isotype switching and B-cell survival, our data implicate TWEAK as a disease-susceptibility gene for a humoral immunodeficiency.     

Host defense mechanisms in invasive candidiasis originating in the GI tract

Evaluation of: Koh AY, Köhler JR, Coggshall KT, Van Rooijen N, Pier GB. Mucosal damage and neutropenia are required for Candida albicans dissemination. PLoS Pathog. 4(2), e35 (2008).

Candida spp. rank among the leading causative agents of nosocomial infections. The increasing number of patients at risk of invasive candidiasis makes a rise in the incidence of this fungal infection expected. Disruption of GI tract integrity and ablation of immune cell populations, such as those resulting from cancer chemotherapy, are recognized as key factors leading to fungal dissemination. However, the individual role of these immune barriers in preventing Candida host colonization and invasion are yet to be fully understood. This article evaluates recently published results on a new murine model of systemic candidiasis originating in the GI tract that might prove a valuable setting for the accurate study of host immune mechanisms, fungal virulence factors and novel therapeutic approaches.     

CAMPATH (alemtuzumab) for the treatment of chronic lymphocytic leukemia and beyond

CAMPATH^® (CAMPATH-1H, alemtuzumab, MabCAMPATH), is a lymphocyte-depleting humanized monoclonal antibody that was recently approved in the USA and Europe for the treatment of chronic lymphocytic leukemia (CLL). It targets CD52 – a small glycosylphosphatidylinositol-anchored glycoprotein that is highly expressed on normal T- and B-lymphocytes and on a large proportion of lymphoid cell malignancies – but not on hematopoietic progenitor cells. CAMPATH was shown to be effective against CLL refractory to chemotherapy with an acceptable toxicity profile. CAMPATH is also active against T-cell prolymphocytic leukemia and has been extensively used to prevent graft-versus-host disease associated with bone marrow transplantation. CAMPATH is owned by ILEX Pharmaceuticals LP and distributed by Schering AG and its US affiliate Berlex Laboratories.     

Haematological manifestations of COVID-19: From cytopenia to coagulopathy

Emerging data from the management of patients with coronavirus disease 2019 (COVID-19) suggests multi-systemic involvement, including the hemopoietic system. The haematological manifestations of COVID-19 include blood count anomalies notably lymphopenia and neutrophilia which are of prognostic significance. Hyperferritinemia and elevated lactate dehydrogenase have also been associated with increased mortality. Furthermore, there is considerable evidence of a distinct coagulopathy associated with COVID-19 characterised by elevated D-dimers and an increased risk of thrombotic events. This comprehensive review summarises the latest evidence from published studies and discusses the implications of the various haematological manifestations of COVID-19 with a view to guiding clinical management and risk stratification in this rapidly evolving pandemic.     

Screening newborns for primary T-cell immunodeficiencies: consensus and controversy

Newborn screening for early identification of T-cell lymphopenia and severe combined immunodeficiency has recently been recommended as an addition to the newborn screening programs in all states. This article will review the evidence supporting the use of this newborn screening test, and will outline the barriers to nationwide implementation, which include issues specific to this test and controversies regarding newborn screening in general.     

Modified-Live Feline Calicivirus Vaccination Reduces Viral RNA Loads,Duration of RNAemia,and the Severity of Clinical Signs after Heterologous Feline Calicivirus Challenge

Feline calicivirus (FCV) is a common cat virus causing clinical signs such as oral ulcerations, fever, reduced general condition, pneumonia, limping and occasionally virulent-systemic disease. Efficacious FCV vaccines protect against severe disease but not against infection. FCV is a highly mutagenic RNA virus whose high genetic diversity poses a challenge in vaccine design. The use of only one modified-live FCV strain over several decades might have driven the viral evolution towards more vaccine-resistant variants. The present study investigated the clinical signs, duration, and amount of FCV shedding, RNAemia, haematological changes and acute phase protein reaction in SPF cats after subcutaneous modified-live single strain FCV vaccination or placebo injection and two subsequent oronasal heterologous FCV challenge infections with two different field strains. Neither clinical signs nor FCV shedding from the oropharynx and FCV RNAemia were detected after vaccination. After the first experimental infection, vaccinated cats had significantly lower clinical scores, less increased body temperature and lower acute phase protein levels than control cats. The viral RNA loads from the oropharynx and duration and amount of RNAemia were significantly lower in the vaccinated animals. No clinical signs were observed in any of the cats after the second experimental infection. In conclusion, FCV vaccination was beneficial for protecting cats from severe clinical signs, reducing viral loads and inflammation after FCV challenge.     

Safety and efficacy of treatment using interleukin‐2 in a patient with idiopathic CD4+ lymphopenia and Mycobacterium avium‐intracellulare

We present the case of a 39‐year‐old white man with a Myobacterium avium‐intracellulare pulmonary infection found to have a CD4⁺ count of 172 cells/mm³ and diagnosed subsequently with idiopathic CD4⁺ lymphopenia (ICL). After receiving clathromycin for 4 months with minimal improvement, the patient was started on pegylated subcutaneous interleukin (IL)‐2 at 600 000 units daily. Later, he received incrementally higher pegylated IL‐2 doses until he reached a maintenance dose 3 months later of 11 million units weekly divided into three equal doses. After 5 months of therapy, the patient's chronic cough resolved completely, sputum cultures became negative for Myobacterium avium‐intracellulare and the CD4⁺ T cell count increased to 553 cells/mm³. After 35 months of well‐tolerated IL‐2 treatments and no recurrence of any opportunistic infections, IL‐2 treatment was stopped. CD4⁺ counts 6 and 9 months after discontinuing IL‐2 treatment were 596 and 378 cells/mm³ respectively, and he remains asymptomatic. This report supports IL‐2 treatment for ICL‐associated opportunistic infections as a safe and potentially efficacious treatment option, especially when combined with more traditional treatment regimens.