PURPOSE: Heterozygous mutations in CTLA4 lead to an inborn error of immunity characterized by immune dysregulation and immunodeficiency, known as CTLA-4 insufficiency. Cohort studies on CTLA4 mutation carriers showed a reduced penetrance (around 70%) and variable disease expressivity, suggesting the presence of modifying factors. It is well studied that infections can trigger autoimmunity in humans, especially in combination with a genetic predisposition. METHODS: To investigate whether specific infections or the presence of specific persisting pathogens are associated with disease onset or severity in CTLA-4 insufficiency, we have examined the humoral immune response in 13 CTLA4 mutation carriers, seven without clinical manifestation and six with autoimmune manifestations, but without immunoglobulin replacement therapy against cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes simplex virus 1/2 (HSV 1/2), parvovirus B19 and Toxoplasma gondii. Additionally, we have measured FcγRIII/CD16A activation by EBV-specific IgG antibodies to examine the functional capabilities of immunoglobulins produced by CTLA4 mutation carriers. RESULTS: The seroprevalence between affected and unaffected CTLA4 mutation carriers did not differ significantly for the examined pathogens. Additionally, we show here that CTLA4 mutation carriers produce EBV-specific IgG, which are unimpaired in activating FcγRIII/CD16A. CONCLUSIONS: Our results show that the investigated pathogens are very unlikely to trigger the disease onset in CTLA-4-insufficient individuals, and their prevalence is not correlated with disease severity or expressivity.

• Klíčová slova
• cytotoxic T-lymphocyte antigen 4 (CTLA-4), disease modifiers, immune dysregulation, immunodeficencies, inborn errors of immunity (IEI),
• MeSH
• antigen CTLA-4 genetika   MeSH
• imunoglobulin G MeSH
• infekce virem Epsteina-Barrové * komplikace   epidemiologie   MeSH
• lidé MeSH
• protilátky virové MeSH
• séroepidemiologické studie MeSH
• virus Epsteinův-Barrové * fyziologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antigen CTLA-4 MeSH
• imunoglobulin G MeSH
• protilátky virové MeSH

This contribution reports the case of a young female patient with a cytotoxic T-lymphocyte antigen 4 (CTLA-4) heterozygous missense mutation giving rise to a broad range of autoimmune diseases, including central nervous system inflammation presenting as disseminated intramedullary and infiltrating brain lesions on MRI. Multiple sclerosis was one of the diagnoses considered. CTLA-4 is a negative immune regulator essential for the function of regulatory T-cells, themselves responsible for maintaining self-tolerance and immune homeostasis. Heterozygous germline mutations in CTLA-4 may lead to an autosomal dominant immune dysregulation syndrome with highly variable phenotype, including various immunodeficiency and autoimmune diseases, along with neurological manifestations.

• Klíčová slova
• Autoimmunity, CTLA-4 antigen, Demyelinating diseases, Genetic diseases, T-lymphocytes,
• MeSH
• antigen CTLA-4 genetika   MeSH
• autoimunitní nemoci * MeSH
• imunologická tolerance MeSH
• lidé MeSH
• mutace MeSH
• regulační T-lymfocyty MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• Názvy látek
• antigen CTLA-4 MeSH

BACKGROUND: Heterozygous germline mutations in cytotoxic T lymphocyte-associated antigen-4 (CTLA4) impair the immunomodulatory function of regulatory T cells. Affected individuals are prone to life-threatening autoimmune and lymphoproliferative complications. A number of therapeutic options are currently being used with variable effectiveness. OBJECTIVE: Our aim was to characterize the responsiveness of patients with CTLA-4 insufficiency to specific therapies and provide recommendations for the diagnostic workup and therapy at an organ-specific level. METHODS: Clinical features, laboratory findings, and response to treatment were reviewed retrospectively in an international cohort of 173 carriers of CTLA4 mutation. Patients were followed between 2014 and 2020 for a total of 2624 months from diagnosis. Clinical manifestations were grouped on the basis of organ-specific involvement. Medication use and response were recorded and evaluated. RESULTS: Among the 173 CTLA4 mutation carriers, 123 (71%) had been treated for immune complications. Abatacept, rituximab, sirolimus, and corticosteroids ameliorated disease severity, especially in cases of cytopenias and lymphocytic organ infiltration of the gut, lungs, and central nervous system. Immunoglobulin replacement was effective in prevention of infection. Only 4 of 16 patients (25%) with cytopenia who underwent splenectomy had a sustained clinical response. Cure was achieved with stem cell transplantation in 13 of 18 patients (72%). As a result of the aforementioned methods, organ-specific treatment pathways were developed. CONCLUSION: Systemic immunosuppressants and abatacept may provide partial control but require ongoing administration. Allogeneic hematopoietic stem cell transplantation offers a possible cure for patients with CTLA-4 insufficiency.

• Klíčová slova
• CTLA-4, HSCT, LRBA, abatacept, common variable immunodeficiency, diagnosis, primary immunodeficiency, rituximab, sirolimus, treatment,
• MeSH
• agamaglobulinemie etiologie   MeSH
• antigen CTLA-4 nedostatek   genetika   MeSH
• autoimunitní nemoci etiologie   MeSH
• dítě MeSH
• dospělí MeSH
• genetické asociační studie MeSH
• homologní transplantace MeSH
• intersticiální plicní nemoci etiologie   MeSH
• kojenec MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• předškolní dítě MeSH
• senioři MeSH
• syndromy imunologické nedostatečnosti komplikace   genetika   terapie   MeSH
• transplantace hematopoetických kmenových buněk MeSH
• zárodečné mutace * MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• kojenec MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antigen CTLA-4 MeSH
• CTLA4 protein, human MeSH Prohlížeč

BACKGROUND: Cytotoxic T-lymphocyte antigen 4 (CTLA-4) insufficiency causes a primary immune regulatory disorder characterized by lymphoproliferation, dysgammaglobulinemia, and multiorgan autoimmunity including cytopenias and colitis. OBJECTIVE: We examined the outcome of hematopoietic stem cell transplantation (HSCT) for CTLA-4 insufficiency and study the impact of pre-HSCT CTLA-4 fusion protein (CTLA-4-Ig) therapy and pre-HSCT immune dysregulation on survival and immunologic outcome. METHODS: This was a retrospective study of HSCT for CTLA-4 insufficiency and 2q33.2-3 deletion from the European Society for Blood and Marrow Transplantation Inborn Errors Working Party. Primary end points were overall survival (OS) and disease- and chronic graft-versus-host disease-free survival (DFS). Secondary end point was immunologic outcome assessed by immune dysregulation disease activity (IDDA) score. RESULTS: Forty patients were included over a 25-year period. Before HSCT, 60% received CTLA-4-Ig, and median (range) IDDA score was 23.3 (3.9-84.0). Median (range) age at HSCT was 14.2 (1.3-56.0) years. Patients received peripheral blood stem cell (58%) or marrow (43%) from a matched unrelated donor (75%), mismatched unrelated donor (12.5%), or matched family donor (12.5%). Median (range) follow-up was 3 (0.6-15) years, and 3-year OS was 76.7% (58-87%) and DFS was 74.4% (54.9-86.0%). At latest follow-up, disease of 28 of 30 surviving patients was in disease-free remission with median IDDA reduction of 16. Probability of OS and DFS was greater in patients with lower disease activity before HSCT (IDDA < 23, P = .002 and P = .006, respectively). CTLA-4-Ig receipt did not influence OS or DFS. Cause of death was transplant related in 7 of 8 patients. CONCLUSION: HSCT is an effective therapy to prevent ongoing disease progression and morbidity, with improving survival rates over time and in patients with lower pre-HSCT disease activity.

• Klíčová slova
• Allogeneic HSCT, CTLA-4, abatacept, belatacept, primary immune regulatory disorder,
• MeSH
• antigen CTLA-4 * genetika   MeSH
• dítě MeSH
• dospělí MeSH
• kojenec MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• nemoc štěpu proti hostiteli MeSH
• předškolní dítě MeSH
• retrospektivní studie MeSH
• transplantace hematopoetických kmenových buněk * MeSH
• výsledek terapie MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• kojenec MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Evropa MeSH
• Názvy látek
• antigen CTLA-4 * MeSH
• CTLA4 protein, human MeSH Prohlížeč

Supraphysiological levels of IL-7 induce increase counts of pre-B cells, naive T cells and memory phenotype CD8+ T cells. Immunocomplexes of IL-7 and αIL-7 mAb M25 (IL-7/M25) were described as IL-7 superagonist in vivo. Thus, treatment of mice with IL-7/M25 remarkably increases the size of the T cell pool. We decided to use IL-7/M25 in order to expand the T cell population prior to the administration of αCTLA-4 and αPD-1 mAbs in tumor-bearing mice and in turn boost the immunotherapy based on a combination of CTLA-4 and PD-1 blockage. We found that just four doses of IL-7/M25 increased the absolute numbers of splenocytes approximately fivefold and significantly shifted the CD4+:CD8+ T cell ratio in favor of CD8+ T cells. There was also a substantive increase in relative counts of memory phenotype CD8+ T cells (approximately threefold) within CD8+ T cells but a significant decrease (approximately 30%) in relative counts of Treg cells within CD4+ T cells. All these data suggest that IL-7/M25 offer a suitable approach to potentiate tumor immunotherapy through CTLA-4 and PD-1 blockage. Unexpectedly, IL-7/M25 significantly abrogated the antitumor activity of αCTLA-4 plus αPD-1 mAbs in the following mouse tumor models: MC-38 and CT26 colon carcinoma and B16F10 melanoma. This paradoxical effect of IL-7/M25 on the antitumor activity of CTLA-4 and PD-1 blockage was not mediated via either increased levels of IL-10 or TGF-β in the sera or increased counts of IL-10-producing B or T cells in the spleen of mice injected with IL-7/M25. Thus, our work shows that caution should be exercised when combining two immunotherapy approaches together.

• Klíčová slova
• Antitumor activity, CTLA-4, IL-7, IL-7 immunocomplexes, Immunotherapy, PD-1,
• MeSH
• antigen CTLA-4 imunologie   MeSH
• antigeny CD279 imunologie   MeSH
• antitumorózní látky imunologie   MeSH
• CD4-pozitivní T-lymfocyty imunologie   MeSH
• CD8-pozitivní T-lymfocyty imunologie   MeSH
• imunoterapie metody   MeSH
• interleukin-10 imunologie   MeSH
• interleukin-7 imunologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• melanom imunologie   MeSH
• modely nemocí na zvířatech MeSH
• monoklonální protilátky imunologie   MeSH
• myši inbrední BALB C MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory tračníku imunologie   MeSH
• regulační T-lymfocyty imunologie   MeSH
• transformující růstový faktor beta imunologie   MeSH
• zvířata MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antigen CTLA-4 MeSH
• antigeny CD279 MeSH
• antitumorózní látky MeSH
• CTLA4 protein, human MeSH Prohlížeč
• IL7 protein, human MeSH Prohlížeč
• interleukin-10 MeSH
• interleukin-7 MeSH
• monoklonální protilátky MeSH
• PDCD1 protein, human MeSH Prohlížeč
• transformující růstový faktor beta MeSH

Cluster of differentiation (CD) 80 is mainly expressed in immune cells but can also be found in several types of cancer cells. This molecule may either activate or inhibit immune reactions. Here, we determined the immunosuppressive role of CD80 in the tumor microenvironment by CRISPR/Cas9-mediated deactivation of the corresponding gene in the mouse oncogenic TC-1 cell line. The tumor cells with deactivated CD80 (TC-1/dCD80-1) were more immunogenic than parental cells and induced tumors that gained sensitivity to cytotoxic T-lymphocyte antigen 4 (CTLA-4) blockade, as compared with the TC-1 cells. In vivo depletion experiments showed that the deactivation of CD80 switched the pro-tumorigenic effect of macrophages observed in TC-1-induced tumors into an anti-tumorigenic effect in TC-1/dCD80-1 tumors and induced the pro-tumorigenic activity of CD4+ cells. Moreover, the frequency of lymphoid and myeloid cells and the CTLA-4 expression by T helper (Th)17 cells were increased in TC-1/dCD80-1- compared with that in the TC-1-induced tumors. CTLA-4 blockade downregulated the frequencies of most immune cell types and upregulated the frequency of M2 macrophages in the TC-1 tumors, while it increased the frequency of lymphoid cells in TC-1/dCD80-1-induced tumors. Furthermore, the anti-CTLA-4 therapy enhanced the frequency of CD8+ T cells as well as CD4+ T cells, especially for a Th1 subset. Regulatory T cells (Treg) formed the most abundant CD4+ T cell subset in untreated tumors. The anti-CTLA-4 treatment downregulated the frequency of Treg cells with limited immunosuppressive potential in the TC-1 tumors, whereas it enriched this type of Treg cells and decreased the Treg cells with high immunosuppressive potential in TC-1/dCD80-1-induced tumors. The immunosuppressive role of tumor-cell-expressed CD80 should be considered in research into biomarkers for the prediction of cancer patients' sensitivity to immune checkpoint inhibitors and for the development of a tumor-cell-specific CD80 blockade.

• Klíčová slova
• CD80, CTLA-4, PD-L1, cancer, immune checkpoint blockade, tumor-infiltrating lymphocytes,
• Publikační typ
• časopisecké články MeSH

Over the past several years, many important changes in the treatment of metastatic melanoma have occurred. New treatment options have been discovered to exploit inhibition of immune checkpoints for promotion of antitumor immune response. Recent results of clinical studies with anti-CTLA 4 and anti-PD 1 monoclonal antibodies show the ability of immunotherapy to extend progression free survival and overall survival in patients with metastatic melanoma when compared to chemotherapy and other therapeutic methods. This article focuses on efficacy and safety of these immunotherapeutic approaches and considered biomarkers of tumor response.

• MeSH
• antigen CTLA-4 antagonisté a inhibitory   MeSH
• antigeny CD279 antagonisté a inhibitory   MeSH
• lidé MeSH
• melanom farmakoterapie   imunologie   MeSH
• monoklonální protilátky terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• antigen CTLA-4 MeSH
• antigeny CD279 MeSH
• monoklonální protilátky MeSH
• PDCD1 protein, human MeSH Prohlížeč

BACKGROUND: Malignant melanoma is a rare malignancy in the pediatric population. Etiology is usually unknown. Clinical symptoms are nonspecific, clinical behavior and biology features may differ from those in an adult population. The most important prognostic factor is spread of disease. Surgical resection is treatment of choice for localized melanoma. Advanced and metastatic melanoma is still an incurable disease. CASE: We are presenting an eight-year- old boy with metastatic malignant melanoma of unknown origin based on TP53 mutation (Li Fraumeni syndrome). He underwent surgery and adjuvant chemotherapy (temozolomide as single agent). Complete remission was achieved at the end of treatment. Two years after the end of therapy (and 31 months from diagnosis) he developed metastatic progression to the lungs. He has received immunotherapy with ipilimumab, according to our knowledge as the first child under the age of 12 in Europe. He completed three courses of ipilimumab, with irAE (immune related adverse event) grade III during the first course of anti CTLA 4. Therefore, further doses of ipilimumab were given with corticoids and antihistamines as premedication. Also, asymptomatic thyreoiditis grade II has been confirmed. The best documented treatment response is stable disease. Performance status was excellent. Three years since the first progression, he developed further massive progression to the lungs. Second line immunotherapy with anti-PD 1 monoclonal antibody (pembrolizumab) is currently going on. So far, the overall survival of the patient is 74 months. CONCLUSION: The presented case study supports the administration of immunotherapy in children younger than 12 years. Therapeutic effect has led to significant overall survival with tolerable toxicity. The problem remains significantly limited number of pediatric clinical trials using immunotherapy.

• MeSH
• antigen CTLA-4 antagonisté a inhibitory   MeSH
• dítě MeSH
• ipilimumab MeSH
• lidé MeSH
• melanom farmakoterapie   sekundární   MeSH
• monoklonální protilátky terapeutické užití   MeSH
• tolerance léku MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• Názvy látek
• antigen CTLA-4 MeSH
• ipilimumab MeSH
• monoklonální protilátky MeSH

BACKGROUND: Immunotherapy is an effective way to treat many diseases associated with disorders of the immune system by modulating immune response. It involves several ways of manipulating the immune system, which either suppress the immune response or, on the contrary, stimulates it. Immunotherapy is currently of immense importance not only in the context of the treatment of autoimmune diseases and immunodeficiencies, but it is also a promising method for treating cancer. Efforts to use the bodys own anti-tumor response have led to the discovery of alternative treatments for cancer. PURPOSE: The aim of this paper is to provide a literature review focused on the current possibilities of cancer immunotherapy. In addition to classical procedures such as chemotherapy and radiotherapy, treatments consisting of adoptive cell therapy and blockade of immune checkpoints are being increasingly indicated. The latest form of adoptive cell therapy is the use of T-lymphocytes expressing chimeric antigen receptors. This type of treatment is indicated for hematological cancers. In recent years, a new approach to the treatment of cancer has emerged using blockade of immune checkpoints by monoclonal antibodies. At present, antitumor therapy focuses on blocking of inhibitory molecules - cytotoxic T-lymfocyte antigen 4 (CTLA-4) and programmed cell death 1 (PD-1). Administration of anti-CTLA-4 receptor specific monoclonal antibodies blocks binding between CTLA-4 receptors and B7 ligands, thereby preventing inhibition of activated cytotoxic T cells. Another type of checkpoints of the immune response include PD-1 molecules expressed on the surface of T-lymphocytes, B-lymphocytes, but also on the surface of myeloid cells. Blockade of PD-1 receptors and PD-L1 ligands prevents the inhibition of T-lymphocytes by tumor cells, leading to an increase in the immune systems ability to recognize tumor cells and subsequently destroy them. Blockade of PD-1 receptors and PD-L1 ligands prevents the inhibition of T-lymphocytes by tumor cells, leading to an increased immune response to the recognition of tumor cells and their subsequent destruction. An alternative form of tumor treatment is the administration of tumor vaccines and tumor-specific monoclonal antibodies (mAbs). The use of mAbs to kill tumors requires the expression of tumor-specific antigens on the surface of tumor cells. Through these receptors, mAb targets cytotoxic cells, toxins, drugs, or radioisotopes to tumor cells and thereby destroys them. Also, mAbs are able to block angiogenesis, which is crucial in tumor cell proliferation.

• Klíčová slova
• CTLA-4, PD-1, Vaccines, adoptive cell therapy, immunotherapy, monoclonal antibody, tumor, tumour,
• MeSH
• antigen CTLA-4 MeSH
• antigeny CD274 MeSH
• antigeny CD279 MeSH
• antitumorózní látky * farmakologie   MeSH
• imunoterapie metody   MeSH
• lidé MeSH
• monoklonální protilátky MeSH
• nádory * patologie   MeSH
• protinádorové látky imunologicky aktivní * terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• antigen CTLA-4 MeSH
• antigeny CD274 MeSH
• antigeny CD279 MeSH
• antitumorózní látky * MeSH
• monoklonální protilátky MeSH
• protinádorové látky imunologicky aktivní * MeSH

[This corrects the article DOI: 10.3389/fimmu.2022.1011646.].

• Klíčová slova
• cytotoxic T-lymphocyte antigen 4 (CTLA-4), disease modifiers, immune dysregulation, immunodeficencies, inborn errors of immunity (IEI),
• Publikační typ
• tisková chyba MeSH