T-cell Deficit Research Articles

Allogeneic, off-the-shelf, SARS-CoV-2-specific T cells (ALVR109) for the treatment of COVID-19 in high-risk patients.

Defects in T-cell immunity to SARS-CoV-2 have been linked to an increased risk of severe COVID-19 (even after vaccination), persistent viral shedding and the emergence of more virulent viral variants. To address this T-cell deficit, we sought to prepare and cryopreserve banks of virus-specific T cells, which would be available as a partially HLA-matched, off-the-shelf product for immediate therapeutic use. By interrogating the peripheral blood of healthy convalescent donors, we identified immunodominant and protective T-cell target antigens, and generated and characterized polyclonal virus-specific T-cell lines with activity against multiple clinically important SARS-CoV-2 variants (including 'delta' and 'omicron'). The feasibility of making and safely utilizing such virus-specific T cells clinically was assessed by administering partially HLA-matched, third-party, cryopreserved SARS-CoV-2-specific T cells (ALVR109) in combination with other antiviral agents to four individuals who were hospitalized with COVID-19. This study establishes the feasibility of preparing and delivering off-the-shelf, SARS-CoV-2-directed, virus-specific T cells to patients with COVID-19 and supports the clinical use of these products outside of the profoundly immune compromised setting (ClinicalTrials.gov number, NCT04401410).

Naïve T-cell Deficits at Diagnosis and after Chemotherapy Impair Cell Therapy Potential in Pediatric Cancers.

Translational data on chimeric antigen receptor (CAR) T-cell trials indicate that the presence of naïve T cells in the premanufacture product is important to clinical response and persistence. In anticipation of developing CAR trials for other tumors, we investigated the T-cell distribution from children with solid tumors and lymphomas at diagnosis and after every cycle of chemotherapy. We found that patients with T cells enriched for naïve and stem central memory cells expanded well in vitro, but the majority of tumor types showed chemotherapy-related depletion of early lineage cells with a corresponding decline in successful ex vivo stimulation response. Unexpectedly, many pediatric patients with solid tumors had low numbers of naïve T cells prior to any therapy. These data indicate the ex vivo manufacture of CAR T cells may need to be customized based on the nature of T cells available in each disease type. SIGNIFICANCE: Cumulative chemotherapy cycles deplete naïve T cells in many pediatric cancer regimens, reducing expansion potential associated with successful adoptive cellular therapies. Naïve T-cell deficits can be seen at diagnosis as well, implying immune deficits that exist prior to chemotherapy, which may also affect the development of immune-based therapies.See related commentary by Leick and Maus, p. 466.This article is highlighted in the In This Issue feature, p. 453.

Wishing on a CAR: Understanding the Scope of Intrinsic T-cell Deficits in Patients with Cancer.

Treatment with chimeric antigen receptor T cells has led to impressive and durable responses in adult and pediatric malignancies refractory to conventional therapy; however, only patients with a handful of cancers have responded thus far and significant disparities exist between the response rates of pediatric and adult patients. A new extensive analysis of pediatric patient T-cell subsets at diagnosis and throughout the patients' chemotherapy courses in a variety of solid and hematologic malignancies sheds new light on the intrinsic T-cell deficits that may be partly to blame.See related article by Das et al., p. 492.

Single-Cell Analysis Identifies Thymic Maturation Delay in Growth-Restricted Neonatal Mice.

Fetal growth restriction (FGR) causes a wide variety of defects in the neonate which can lead to increased risk of heart disease, diabetes, anxiety and other disorders later in life. However, the effect of FGR on the immune system, is poorly understood. We used a well-characterized mouse model of FGR in which placental Igf-2 production is lost due to deletion of the placental specific Igf-2 P0 promotor. The thymi in such animals were reduced in mass with a ~70% reduction in cellularity. We used single cell RNA sequencing (Drop-Seq) to analyze 7,264 thymus cells collected at postnatal day 6. We identified considerable heterogeneity among the Cd8/Cd4 double positive cells with one subcluster showing marked upregulation of transcripts encoding a sub-set of proteins that contribute to the surface of the ribosome. The cells from the FGR animals were underrepresented in this cluster. Furthermore, the distribution of cells from the FGR animals was skewed with a higher proportion of immature double negative cells and fewer mature T-cells. Cell cycle regulator transcripts also varied across clusters. The T-cell deficit in FGR mice persisted into adulthood, even when body and organ weights approached normal levels due to catch-up growth. This finding complements the altered immunity found in growth restricted human infants. This reduction in T-cellularity may have implications for adult immunity, adding to the list of adult conditions in which the in utero environment is a contributory factor.

T-cell Dysfunction in Glioblastoma: Applying a New Framework.

A functional, replete T-cell repertoire is an integral component to adequate immune surveillance and to the initiation and maintenance of productive antitumor immune responses. Glioblastoma (GBM), however, is particularly adept at sabotaging antitumor immunity, eliciting severe T-cell dysfunction that is both qualitative and quantitative. Understanding and countering such dysfunction are among the keys to harnessing the otherwise stark potential of anticancer immune-based therapies. Although T-cell dysfunction in GBM has been long described, newer immunologic frameworks now exist for reclassifying T-cell deficits in a manner that better permits their study and reversal. Herein, we divide and discuss the various T-cell deficits elicited by GBM within the context of the five relevant categories: senescence, tolerance, anergy, exhaustion, and ignorance. Categorization is appropriately made according to the molecular bases of dysfunction. Likewise, we review the mechanisms by which GBM elicits each mode of T-cell dysfunction and discuss the emerging immunotherapeutic strategies designed to overcome them. Clin Cancer Res; 24(16); 3792-802. ©2018 AACR.

A pilot study on immuno-psychiatry in the 22q11.2 deletion syndrome: A role for Th17 cells in psychosis?

BackgroundA growing body of evidence supports a role for immune alterations in Schizophrenia Spectrum Disorders (SSD). A high prevalence (25–40%) of SSD has been found in patients with 22q11.2 deletion syndrome (22q11.2DS), which is known for T-cell deficits due to thymus hypoplasia. This study is the first to explore the association between the T-cell subsets and psychotic symptoms in adults with 22q11.2DS. Methods34 individuals (aged 19–38 yrs.) with 22q11.2DS and 34 healthy age- and gender matched control individuals were included. FACS analysis of the blood samples was performed to define T-cell subsets. Ultra-high risk for psychosis or diagnosis of SSD was determined based on CAARMS interviews and DSM-5 criteria for SSD. Positive psychotic symptom severity was measured based on the PANSS positive symptoms subscale. ResultsA partial T-cell immune deficiency in 22q11.2DS patients was confirmed by significantly reduced percentages of circulating T and T-helper cells. Significantly higher percentages of inflammatory Th1, Th17, and memory T-helper cells were found in adults with 22q11.2DS. Most importantly an increased Th17 percentage was found in adults with psychotic symptoms as compared to non-psychotic adults with 22q11.2DS, and Th17 percentage were related to the presence of positive psychotic symptoms. ConclusionsGiven the literature on the role of T cells and in particular of Th17 cells and IL-17 in hippocampus development, cognition and behavior, these results support the hypothesis for a role of Th17 cells in the development and/or regulation of psychotic symptoms in 22q11.2DS. This pilot study underlines the importance to further study the role of T-cell defects and of Th17 cells in the development of psychiatric symptoms. It also supports the possibility to use 22q11.2DS as a model to study T-cell involvement in the development of SSD.

Regulating the T-Cell Immune Response Toward the H99 Strain of Cryptococcus neoformans

Regulating the T-Cell Immune Response Toward the H99 Strain of Cryptococcus neoformans

Despite Absence of Measurable Immune Responses against Adenovirus in the First 100 Days After Unrelated Umbilical Cord Blood Transplant in Vitro amplification Strategies Can Unveil Hexon and Penton-Specific Immunity.

Abstract 4640Unrelated cord blood transplantation (UCBT) has become a life saving modality of hematopoietic cell transplantation (HCT) for those cancer patients who lack HLA-matched sibling donors. However, success after UCBT is limited by the high incidence of opportunistic infections (OI), most of which are viral and typically detected < 3 months after UCBT. A minority of UCBT patients with evidence of viral infection/reactivation post-transplant actually resolve their disease without antiviral therapy. Since these infections are largely controlled by T-cell immunity this suggests that in vivo T-cell priming may occur despite immunosuppressive drugs and functional T-cell deficits and protective antiviral immunity can be attained once a threshold number of antiviral T-cells have been achieved. To determine whether this was the case we collected PBMCs from 10 UCBT patients who underwent myeloablative regimens and were diagnosed with adenovirus infection (defined as positive PCR at least twice and/or viral culture in blood and/or stool and/or nasopharynx). Samples were collected a median of 88 days (range 37-209 days) post-transplant at first indication of Adv positivity (blood PCR + in 5/10 patients at a mean of ∼110,000 copies/ml, median of 350, range 100-1×106 copies/ml, 4 patients positive in stool only, one patient + in respiratory tract only). The median age of patients was 4.6 years (range 2.0-16.6y). Eight (8) out of ten (10) patients had grade 2-4 acute GVHD prior to the studies, while the other two patients had grade I.At baseline we were consistently unable to detect T-cells with reactivity against the immunodominant adenoviral virion proteins hexon and penton by IFN-g ELIspot [hexon - median 1.75 spot forming cells (SFC)/2×105 PBMC (range 1-12.5), penton – median 1 SFC)/2×105 PBMC (range 0.5-1)], even though the patients had evidence of active adenovirus infections. However, in 5/10 patients adenovirus-specific T cells could be amplified by a single in vitro stimulation with donor-derived mononuclear cells transduced with a recombinant adenovirus type 5 vector pseudotyped with a type 35 fiber (MOI 200 virus particles (vp) per cell) and culture in the presence of IL4 (1000u/ml). The median hexon-specific T cell frequency in the reactivated cytotoxic T lymphocyte (CTL) lines was 62.5 SFC/2×105 (range 34.5-299.5), and in one patient hexon epitope mapping revealed reactivity against at least four distinct peptides. Penton was also recognized by the CTL lines with a median T-cell frequency of 30 SFC/2×105 (range 26.5-164), with no recognition of control pepmixes. In contrast we were unable to expand adenovirus-reactive T cells from the remaining five patients. Two of three patients with positive ELIspot results from the CTL cultures against both hexon and penton are alive and adenovirus negative without any antiviral agents used at a median of 446 days post-UCBT (range 422-470). Four (4) patients died despite receiving antiviral treatment with Cidofovir. Two of these patients had no detectable antiviral immunity, while the others had only restricted or weak reactivity (reactivity against only one antigen or reactivity below the median SFC values of the responder cohort).To our knowledge this is the first study that analyzes the anti-adenoviral immune response in UCBT recipients with active infection in the early post-transplant period. It appears that in the first 100 days after UCBT, during a time of active immunosuppression, adenovirus-specific T-cells in peripheral blood are consistently (10/10 patients) below the level of detection of conventional IFN-g ELIspot assays. However, dormant immune responses can be amplified in vitro using a single stimulation in the presence of IL4. Furthermore, detection of functional CTL against hexon and penton proteins may be a useful marker to distinguish between those with effective antiviral T cell immunity and those at risk of developing progressive disease. Disclosures:No relevant conflicts of interest to declare.

HIV-1 Infection Impairs the Bronchoalveolar T-Cell Response to Mycobacteria

The risk of developing active tuberculosis in persons with latent Mycobacterium tuberculosis infection is substantially increased shortly after HIV-1 seroconversion. Immune responses in the lung are important to restrict the growth of M. tuberculosis to prevent the development of disease. To investigate innate and adaptive immune responses to M. tuberculosis in bronchoalveolar lavage from HIV-1-infected persons without active tuberculosis. Peripheral blood was drawn and bronchoalveolar lavage (BAL) performed on healthy, HIV-1-uninfected (n = 21) and HIV-1-infected (n = 15) adults. Growth of M. tuberculosis was assessed in monocytes and alveolar macrophages. Cytokine expression by mycobacteria-specific CD4 and CD8 T cells was measured by intracellular cytokine staining or IFN-gamma ELISpot. Mycobacterial growth in monocytes or alveolar macrophages from HIV-1-infected and -uninfected persons did not differ. Total CD4 T-cell frequencies in BAL were lower in HIV-1-infected than in HIV-1-uninfected persons (P < 0.001). Mycobacteria (bacillus Calmette-Guérin)-specific CD4 T-cell responses in BAL were severely impaired: Frequencies of cells expressing IFN-gamma or tumor necrosis factor (TNF)-alpha, as well as polyfunctional cells, expressing IFN-gamma, TNF-alpha, and IL-2 together, were lower in HIV-1-infected persons than in uninfected controls (P < 0.01 for all). In addition to a total CD4 T-cell deficit, the function of mycobacteria-specific CD4 T cells is significantly impaired in the lung of HIV-1-infected persons, which may account for the HIV-1-associated elevated risk for developing tuberculosis.

Impaired Hepatitis C Virus (HCV)-Specific Effector CD8 + T Cells Undergo Massive Apoptosis in the Peripheral Blood during Acute HCV Infection and in the Liver during the Chronic Phase of Infection

A majority of patients infected with hepatitis C virus (HCV) do not sustain an effective T-cell response, and viremia persists. The mechanism leading to failure of the HCV-specific CD8(+) T-cell response in patients developing chronic infection is unclear. We investigated apoptosis susceptibility of HCV-specific CD8(+) T cells during the acute and chronic stages of infection. Although HCV-specific CD8(+) T cells in the blood during the acute phase of infection and in the liver during the chronic phase were highly activated and expressed an effector phenotype, the majority was undergoing apoptosis. In contrast, peripheral blood HCV-specific CD8(+) T cells during the chronic phase expressed a resting memory phenotype. Apoptosis susceptibility of HCV-specific CD8(+) T cells was associated with very high levels of programmed death-1 (PD-1) and low CD127 expression and with significant functional T-cell deficits. Further evaluation of the "death phase" of HCV-specific CD8(+) T cells during acute HCV infection showed that the majority of cells were dying by a process of cytokine withdrawal, mediated by activated caspase 9. Contraction during the acute phase occurred rapidly via this process despite the persistence of the virus. Remarkably, in the chronic phase of HCV infection, at the site of infection in the liver, a substantial frequency of caspase 9-mediated T-cell death was also present. This study highlights the importance of cytokine deprivation-mediated apoptosis with consequent down-modulation of the immune response to HCV during acute and chronic infections.

Regulatory T cells in primary immunodeficiency diseases

Several primary immune deficiency disorders are associated with autoimmunity and malignancy, suggesting a state of immune dysregulation. Here, we review the role of regulatory T-cell deficits in mediating the immune dysregulation associated with certain primary immune deficiency disorder syndromes. Systematic studies in primary immune deficiency disorders and their associated animal models have led to an increased understanding of both central and peripheral tolerance mechanisms, and in particular have yielded new insights into regulatory T-cell function, development and maintenance. Single-gene defects identified in patients with multiple autoimmune phenomena have defined new primary immune deficiency disorder syndromes in which the primary deficit is in the establishment or maintenance of immune tolerance. The disorder that has been most informative with regard to understanding the function and development of regulatory T cells is forkhead box P3 deficiency, known as immune dysregulation, polyendocrinopathy, enteropathy and X-linked syndrome in humans and Scurfy in the mouse. Recent studies in patients with other primary immune deficiency disorders, including autoimmune polyendocrinopathy, candidiasis and ectodermal dystrophy syndrome, CD25 deficiency, STAT5b deficiency, and Wiskott-Aldrich syndrome, have added to our understanding of regulatory T-cell biology. The study of patients with rare primary immune deficiency disorder syndromes provides an unparalleled opportunity to understand mechanisms of autoimmunity and immune tolerance in humans.

Herpes simplex virus type 1 colitis in a patient with common variable immunodeficiency syndrome

We report on a case of herpes simplex virus (HSV) type 1 colitis in a 69-year-old patient with common variable immunodeficiency syndrome. A treatment with polyvalent immunoglobulins was discontinued in April 2001. In March 2004 she developed chronic diarrhoea related to rectosigmoidal and caecal ulcerations. In November 2004, HSV was recovered in tissue culture from colonic biopsies. Valaciclovir was then started, leading the patient to clinical remission at day 4, and continued for a 6-week course (without any secondary antiviral prophylaxis). Colonic biopsies were negative for HSV by tissue culture and PCR within 3 weeks of antiviral treatment. Intravenous polyvalent immunoglobulin infusions were readministered within the third week of antiviral treatment. She has declared no clinical event since this period. Three months after the antiviral treatment was achieved, a rectosigmoidoscopy showed an ad-integrum macroscopic and histological mucosal healing whereas PCR was negative for HSV in the colonic tissue. As a large proportion of patients with common variable immunodeficiency syndrome present not only as a humoral immunodeficiency but also as a defect in the cellular immunity compartment (with T-cell deficits), HSV, as well as cytomegalovirus, should be investigated in patients with common variable immunodeficiency syndrome presenting colitis.

Role of Thymic Output in Regulating CD8 T-Cell Homeostasis during Acute and Chronic Viral Infection

Although it is well documented that CD8 T cells play a critical role in controlling chronic viral infections, the mechanisms underlying the regulation of CD8 T-cell responses are not well understood. Using the mouse model of an acute and chronic lymphocytic choriomeningitis virus (LCMV) infection, we have examined the relative importance of peripheral T cells and thymic emigrants in the elicitation and maintenance of CD8 T-cell responses. Virus-specific CD8 T-cell responses were compared between mice that were either sham thymectomized or thymectomized (Thx) at approximately 6 weeks of age. In an acute LCMV infection, thymic deficiency did not affect either the primary expansion of CD8 T cells or the proliferative renewal and maintenance of virus-specific lymphoid and nonlymphoid memory CD8 T cells. Following a chronic LCMV infection, in Thx mice, although the initial expansion of CD8 T cells was normal, the contraction phase of the CD8 T-cell response was exaggerated, which led to a transient but striking CD8 T-cell deficit on day 30 postinfection. However, the virus-specific CD8 T-cell response in Thx mice rebounded quickly and was maintained at normal levels thereafter, which indicated that the peripheral T-cell repertoire is quite robust and capable of sustaining an effective CD8 T-cell response in the absence of thymic output during a chronic LCMV infection. Taken together, these findings should further our understanding of the regulation of CD8 T-cell homeostasis in acute and chronic viral infections and might have implications in the development of immunotherapy.

Role of TBX1 in human del22q11.2 syndrome

Del22q11.2 syndrome is the most frequent known chromosomal microdeletion syndrome, with an incidence of 1 in 4000-5000 livebirths. It is characterised by a 3-Mb deletion on chromosome 22q11.2, cardiac abnormalities, T-cell deficits, cleft palate facial anomalies, and hypocalcaemia. At least 30 genes have been mapped to the deleted region. However, the association of these genes with the cause of this syndrome is not clearly understood. To test for the chromosomal deletion at 22q11.2, we did fluorescence in-situ hybridisation analysis with ten probes on 22q11.2 in 235 unrelated patients with clinically diagnosed del22q11.2 syndrome. To investigate mutations in the coding sequence of TBX1, we also did genetic analysis in 13 patients from ten families who have the 22q11.2 syndrome phenotype but no detectable deletion of 22q11.2. 96% (225 of 235) of patients had a defined 1.5-3-Mb deletion at 22q11.2. We identified three mutations of TBX1 in two unrelated patients without the 22q11.2 deletion-one with sporadic conotruncal anomaly face syndrome/velocardiofacial syndrome and one with sporadic DiGeorge's syndrome-and in three patients from a family with conotruncal anomaly face syndrome/velocardiofacial syndrome. We did not record these three mutations in 555 healthy controls (1110 chromosomes; p<0.0001). Our results suggest that the TBX1 mutation is responsible for five major phenotypes in del22q11.2 syndrome. Therefore, we conclude that TBX1 is a major genetic determinant of the del22q11.2 syndrome.

The anti-apoptotic activities of Rel and RelA required during B-cell maturation involve the regulation of Bcl-2 expression.

Rel and RelA, individually dispensable for lymphopoiesis, serve unique functions in activated B and T cells. Here their combined roles in lymphocyte development were examined in chimeric mice repopulated with c-rel(-/-) rela(-/-) fetal liver hemopoietic stem cells. Mice engrafted with double-mutant cells lacked mature IgM(lo)IgD(hi) B cells, and numbers of peripheral CD4(+) and CD8(+) T cells were markedly reduced. The absence of mature B cells was associated with impaired survival that coincided with reduced expression of bcl-2 and A1. bcl-2 transgene expression not only prevented apoptosis and increased peripheral B-cell numbers, but also induced further maturation to an IgM(lo)IgD(hi) phenotype. In contrast, the survival of double-mutant T cells was normal and the bcl-2 transgene could not rectify the peripheral T-cell deficit. These findings indicate that Rel and RelA serve essential, albeit redundant, functions during the later antigen-independent stages of B- and T-cell maturation, with these transcription factors promoting the survival of peripheral B cells in part by upregulating Bcl-2.

The peripheral T-cell pool: regulation by non-antigen induced proliferation?

Despite continuous perturbations, the recirculating lymphocyte pool remains relatively constant. Expansion of the pool is compensated for by cell loss. When the T-cell pool is in deficit, either from a congenital defect or an acquired immunodeficiency, T-cell numbers are restored by extrathymic division—a response that occurs without deliberate provocation. We have considered how the recirculating pool may be stably maintained and how a T-cell deficit might be restored to equilibrium. Recent evidence suggests that depleted T-cell compartments are replenished by CD4 T-cell proliferation in the absence of specific antigen, a response that occurs without engaging the T-cell receptor.

Lymphopoiesis, apoptosis, and immune amnesia.

Bone marrow transplant recipients have a functional T-cell deficit long after T-cell counts have returned to normal levels. Early after BMT, T-cell phenotype is predominantly CD45RO+/CD29high/HLA-DR+/CD38high. This profile is associated with activated memory cells in healthy subjects, but also appears on the earliest mature naive T-cells in times of lymphopoietic stress. Most of these cells apoptose in short-term unstimulated culture, suggesting that they would have had a similar fate in vivo. Twelve to 24 months after BMT, CD45RA+/CD29low/HLA-DR-/CD38low T cells increase, apoptosis decreases, and T-cell function normalizes. We hypothesize that in the adult, mature memory T cells regulate their own replacement by rescuing a proportion of newly generated naive cells from apoptosis. Ablation of memory cells consequent to high dose therapy disrupts this process, resulting in a protracted period of high lymphocyte turnover with few cells surviving to make the antigen-driven transition to memory cells. Infection with HIV-1 also eventuates in immune deficiency associated with a loss in CD4+ T cells and dominance of the phenotypic/apoptotic profile which we have associated with lymphopoietic stress. Recent data independently confirm that T-cell turnover is greatly elevated in HIV infection. Catastrophic or chronic depletion of memory T cells due to marrow ablative therapy or HIV-1 infection interferes with memory replacement, substituting short-lived hypofunctional naive T cells which characterize the state of immune amnesia.

Clinical and biological characteristics of malignant lymphomas in HIV-infected patients

THE ACQUIRED IMMUNODE~~CIENCY SYNDROME (AIDS) was described at the beginning of the last decade with the observation of opportunistic infections (especially Pneumocystis pneumonia) and Kaposi’s sarcoma within homosexual men with marked acquired immunosuppression [ 1, 21. Besides homosexual men, other groups (intravenous drug users, haemophiliacs) presented a similar syndrome in the USA and Europe. In Africa, AIDS spread rapidly in young adults of both sexes as well as in infants of infected mothers. In 1983-84, the pathogenic virus was first isolated in France and then in the USA [3, 41. The main targets of the human immunodeficiency virus (HIV) are the T-helper lymphocytes, which are infected through the surface CD4 receptor that is recognised by the viral envelope glycoprotein gp120 [5-71. Some monocytes and macrophages also express the CD4 receptor and may also be infected by HIV [8, 91. The virus causes the destruction of CD4 lymphocytes by direct cytolysis, syncitia formation, as well as by other immune and auto-immune mechanisms [ 10-131. The result is progressive and severe impairment of cellular immunity. In addition to the T-cell deficit, HIV causes important disorders in humoral immunity. HIV proteins trigger B-cell proliferation either in a mitogenic or an antigen-specific manner [14, 151. The mitogenic response may be directly caused by the virus (independently of accessory cells), and also by the release of cytokine, such as interleukin 6 [16, 171. B-cell activation is characteristic of patients with mild as well as severe manifestations of HIV infection [ 181. Infected subjects display increasing serum levels of irnmunoglobulins, circulating immunocomplexes and also an increased number of peripheral lymphocytes spontaneously secreting immunoglobulin [ 19, 201. In addition, seropositive individuals develop a persistent generalised lymphadenopathy (PGL) in approximately 30% of the cases. This lymphadenopathic syndrome is characterised by an exuberant hyperplasia of the germinative centres, where B-cell maturation occurs, with polyclonal B-cell proliferation [21, 221. Severe immunodeficiency together with chronic antigenicimitogenic stimulation has been associated with lymphoid malignancies [23-271. Thus, HIV infection may be considered as a prelymphomatous state. The first cases of Burkitt’s lymphomas (BL) in homosexual men were reported in 1982 [28, 291. In 1983, with the observation of several cases of aggressive non-Hodgkin lymphomas (NHL) in risk groups for AIDS, a definitive relation between NHL and AIDS was established [30]. This association was further confirmed epidemiologically [3 1, 321. In 1985, the inci

Evoked potentials and neurotransmitter metabolism in brain structures during chronic haloperidol administration

Primary obtained triple highly immunogenetic complex consists of nonimmunogenic protein antigen, isolated from the BCG, nontoxic polyelectrolyte and bivalent cuprum ions. Immunization with this complex provides high immunoprotection in the experimented B mice (T-deficit mice) from lethal dissemination BCG. Inoculation of single components of the complex has no protection. Result of these experiments suggest that antigen-polyelectrolyte complexes obtained on the basis of nonimmunogenic protein fraction of the tuberculosis bacilli show the properties of a thymus-independent immunization preparations, and provide immune defense in the T-cell deficit of the immune system.

Alterations of T-Cell Functions During Friend Leukemia Complex Infection: Defective Signal Transduction?

Proliferative and interleukin responses to T-cell mitogens such as concanavalin A (Con A) were rapidly and progressively reduced in BALB/c mice infected with the Friend leukemia complex (FLC) or its helper, Friend murine leukemia virus (F-MuLV). In contrast, a combination of the protein kinase C activator phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA) and the Ca++ ionophore A23187 elicited a normal lymphoproliferative response up to 8 days postinfection (p.i.) and normal interleukin-2 (IL-2) and interferon-gamma responses up to day 14 p.i. Exogenous IL-2 failed to restore the lymphoproliferative response of infected cells regardless of the stimulation used. These results showed that the T-cell deficits may be at least partly attributable to a derangement of the signal transduction pathway leading to activation. Spleen cells passed through nylon wool columns reacquired a normal responsiveness to Con A +/- TPA up to 14 days p.i. The latter finding suggests that the alterations in signal transduction are not caused by primary defect of the responder-T cells but may result from an extrinsic suppressive mechanism.