Biomedical subjects

Mathias Oelke

Publications and source records attributed to Mathias Oelke.

8 recordsLinked to original sources

PubMed2005

Artificial antigen-presenting cells: artificial solutions for real diseases.

Adoptive immunotherapy, which involves the transfer of autologous antigen-specific T cells generated ex vivo, is a promising strategy to treat a variety of life-threatening diseases. Unfortunately, current approaches for generating sufficient numbers of antigen-specific T cells lack the ability to serve as reproducible and economically viable methods. This has spurred the development of both cell- and non-cell-based artificial antigen-presenting cells to alleviate problems associated with peptide-loaded dendritic cells in current approaches to adoptive immunotherapy. Here, we review new strategies for the ex vivo generation of antigen-specific T cells and their clinical application. These new approaches have the potential to spearhead a new era of successful adoptive immunotherapy for cancer and infectious diseases.

Animals↗

PubMed2005

Evaluation of topoisomerase-1-specific CD8+ T-cell response in systemic sclerosis.

Measurement of disease activity in systemic autoimmune disorders is often unreliable, and immunosuppressive therapy is often titrated to crude clinical response and/or onset of complications. Systemic sclerosis (SSc) presents a distinct clinical phenotype associated with specific autoantibodies. Anti-topoisomerase-1 (SCL-70) is selectively detected in 30-60% of subjects with diffuse skin and interstitial lung involvement. Such patients offer an ideal clinical model to characterize and quantify the autoantigen-specific T-cell response and its correlation with disease phenotype and activity. Human leukocyte antigen A2 (HLA-A2)-restricted topo-1 peptides were selected based on an epitope prediction algorithm. For initial studies, the best binder topo-1(262-270) KMLDHEYTT (#262) was used alone or loaded onto an artificial antigen-presenting platform generated by coupling a dimeric major histocompatibility complex-immunoglobulin G fusion protein (HLA-A2-Ig) and anti-CD28 antibodies onto magnetic beads (artificial antigen-presenting cells). Blood samples (100 microL) from HLA-A2+ SSc patients and cytomegalovirus (CMV) seropositive healthy control subjects were tested in an intracellular cytokine staining assay. Gamma interferon production by CD8+ T cells was measured after stimulation with peptide #262, CMVpp65, or MART-1 (irrelevant peptide). In two of five SCL-70+ patients, peptide #262-loaded aAPCs induced a specific CD8+ T-cell response (0.45% +/- 0.23% of total CD8+ cells). This response was not observed in the seven SCL-70- (five SSc and two CMV+) control subjects studied (0.03% +/- 0.02%). Interestingly, bronchoalveolar lavage fluid obtained from one topo-1-responsive SSc patient who had worsening respiratory function and active alveolitis showed striking enrichment of topo-1-specific CD8+ T cells (3.94%). This small-volume ex vivo assay may prove to be a sensitive and specific tool to assess disease activity and to monitor response to therapy in patients with scleroderma.

Autoimmune Diseases↗

PubMed2005

Technological advances in adoptive immunotherapy.

Adoptive immunotherapy is an attractive and elegant strategy for treating a variety of life-threatening diseases. Several approaches have been developed to generate antigen-specific CD4+ and CD8+ T cells for adoptive T-cell therapy in cancer and infectious diseases. Currently, many approaches are based on either the use of autologous peptide pulsed dendritic cells as antigen-presenting cells or nonspecific expansion of T cells. Unfortunately, current approaches lack the ability to serve as reproducible and economically viable methods. Several groups are developing new artificial approaches to overcome problems associated with dendritic cells and the nonspecific expansion of T-cell clones in order to make adoptive immunotherapy more feasible and effective. Thus, by increasing the availability of adoptive immunotherapy, we will be able to better determine the efficacy of the approaches in the treatment of a variety of diseases. In this review, we focus on technological advances that will facilitate adoptive immunotherapy. Specifically, we summarize current strategies which are either based on artificial antigen-presenting cells or on T-cell receptor gene transfer.

Antigen-Presenting Cells↗

PubMed2004

HLA-Ig-based artificial antigen-presenting cells: setting the terms of engagement.

Recent advances in molecular medicine have shown that soluble MHC-multimers can be valuable tools for both the stimulation of as well as the analysis of antigen-specific T cells in vitro. In this review, we describe the use of dimeric major histocompatibility complexes, HLA-Ig, to visualize antigen-specific T cells as well as their potential to stimulate immune responses as part of an artificial antigen-presenting cell (aAPC). The use of HLA-Ig-based aAPC represents an exciting new approach to generate antigen-specific CTL for adoptive immunotherapy that helps to overcome many of the obstacles associated with limitations in current approaches to adoptive immunotherapy.

Animals↗

PubMed2004

Quality and quantity: new strategies to improve immunotherapy of cancer.

Adoptive immunotherapy is a promising approach for the treatment of infectious diseases and cancer. Several lines of research are currently focusing on the development of different technologies to facilitate the induction and expansion of antigen-specific T cells. Here, we discuss two current articles that affect the field of adoptive immunotherapy. One article describes the engineering of artificial antigen-presenting cells, which promise to replace the cumbersome dendritic-cell approach for the in vitro generation of large numbers of antigen-specific T cells. The second development is a description of a new technique for the detection of functionally active antigen-specific T cells, which will enhance the ability to control the quality of the T cells to be used in adoptive immunotherapy. Together, these exciting findings will advance the field of immunotherapy.

Animals↗

PubMed2004

Intracranial aspergillosis in a non-immunocompromised patient treated for muscle-invasive bladder cancer.

We report a case of intracerebral Aspergillosis in a patient undergoing radical cystectomy for the treatment of muscle-invasive bladder cancer who did not reveal any deterioration of the immune system. Aspergillus fumigatus is an ubiquitously present, airborne fungus that tends to infect the upper respiratory tract. However, the latter was not observed in the patient presented. Complications in the form of an involvement of the central nervous system are very rarely recognized as a result of an Aspergillus infection and primarily occur in patients who are not immunologically competent. To our knowledge, we present the first case of intracerebral invasive Aspergillosis in an otherwise healthy patient diagnosed with an urological malignancy.

Aspergillus fumigatus↗

PubMed2003

Ex vivo induction and expansion of antigen-specific cytotoxic T cells by HLA-Ig-coated artificial antigen-presenting cells.

Adoptive immunotherapy holds promise as a treatment for cancer and infectious diseases, but its development has been impeded by the lack of reproducible methods for generating therapeutic numbers of antigen-specific CD8(+) cytotoxic T lymphocytes (CTLs). As a result, there are only limited reports of expansion of antigen-specific CTLs to the levels required for clinical therapy. To address this issue, artificial antigen-presenting cells (aAPCs) were made by coupling a soluble human leukocyte antigen-immunoglobulin fusion protein (HLA-Ig) and CD28-specific antibody to beads. HLA-Ig-based aAPCs were used to induce and expand CTLs specific for cytomegalovirus (CMV) or melanoma. aAPC-induced cultures showed robust antigen-specific CTL expansion over successive rounds of stimulation, resulting in the generation of clinically relevant antigen-specific CTLs that recognized endogenous antigen-major histocompatibility complex complexes presented on melanoma cells. These studies show the value of HLA-Ig-based aAPCs for reproducible expansion of disease-specific CTLs for clinical approaches to adoptive immunotherapy.

Antigen Presentation↗

PubMed2003

Identification of beta-subunit of bacterial RNA-polymerase--a non-species-specific bacterial protein--as target of antibodies in primary biliary cirrhosis.

Several observations suggest that bacteria induce autoimmunity in primary biliary cirrhosis (PBC). Since no PBC-specific bacterial species could be identified, it can be speculated that the triggers are non-species-specific bacterial proteins. This hypothesis would imply that several or even all bacterial species can trigger PBC. Therefore, we investigated whether PBC exhibits immune reactions to non-species-specific bacterial antigens. Yersinia enterocolitica O3 was screened for the presence of proteins that were labeled by immunoblotting using PBC sera. We focused our investigations on a 160-kDa protein, which was further enriched and characterized by partial N-terminal amino acid sequencing. The prevalence of antibodies to this protein was determined by immunoblotting in a variety of diseases. The 160-kDa protein was identified as the beta-subunit of bacterial RNA-polymerase, a highly conserved bacterial protein with a very high degree of sequence identity among all bacterial species. Antibodies to the beta-subunit of bacterial RNA polymerase were specific for this protein. Until now no mammalian protein could be found that cross-reacts with these antibodies. The prevalence of antibodies to the beta-subunit of bacterial RNA polymerase (ARPA) using the protein from Yersinia enterocolitica O3 (serum dilution 1:1000) was: healthy controls (HC, N = 101) 7.9%, primary biliary cirrhosis (PBC, N = 61) 32.8%, autoimmune hepatitis type 1 (AIH, N = 46) 26.1%, alcoholic liver cirrhosis (ALC, N = 44) 9.1%, Crohn's disease (CD, N = 38) 7.9%, ulcerative colitis (UC, N = 24) 8.3%, primary sclerosing cholangitis + UC (PSC/UC, N = 11) 0%, acute yersiniosis (Yers, N = 36) 19.4%, acute infection with Campylobacter jejuni (Camp, N = 10) 0%, acute Q-fever (QF, N = 16) 6.25%, chronic hepatitis C (HCV, N = 39) 7.7%, c-ANCA-positive vasculitis (Vasc, N = 40) 15%, systemic lupus erythematosus (SLE, N = 28) 10.7%, and malaria tropica (MT, N = 24) 16.7%. There was no significant difference between PBC and AIH. The group of autoimmune liver diseases (PBC + AIH, N = 107, 29.9%) differed highly significantly from HC, chronic inflammatory bowel diseases (CD + UC + PSC/UC, N = 73, 6.8%), ALC, and HCV and also differed significantly (P = 0.01) from the group with bacterial and parasitic diseases (Yers + Camp + QF + MT, N = 86,13.95%) and from the group with Vasc + SLE (N = 68,13.2%). Testing of ARPA using the protein from E. coli yielded nearly identical results. In conclusion, an increased prevalence of antibodies to the beta-subunit of bacterial RNA polymerase, a highly conserved non-species-specific bacterial protein, can be found in primary biliary cirrhosis, but also in autoimmune hepatitis type I. These findings do not add an argument for a bacterial trigger of PBC. Rather, they suggest that ARPA belong to the pool of natural antibodies that are up-regulated in autoimmune liver diseases.

Antibodies, Bacterial↗