scholarly journals Prevention of diabetes in BioBreeding/Worcester rats with monoclonal antibodies that recognize T lymphocytes or natural killer cells.

1986 ◽  
Vol 164 (4) ◽  
pp. 1145-1159 ◽  
Author(s):  
A A Like ◽  
C A Biron ◽  
E J Weringer ◽  
K Byman ◽  
E Sroczynski ◽  
...  
Keyword(s):  
T Cells ◽  
Smooth Muscle ◽  
Monoclonal Antibodies ◽  
T Lymphocytes ◽  
Nk Cells ◽  
Pancreatic Beta Cell ◽  
Beta Cell Destruction ◽  
Combined Action ◽  
Prevention Of Diabetes ◽  
Thyroid Colloid

Diabetes-prone BioBreeding/Worcester (BB/Wor) rats received thrice weekly injections of mAb against antigens expressed on the surface of all T cells (OX19), cytotoxic/suppressor, and NK cells (OX8), helper/inducer cells (W3/25, OX35, OX38), and Ia+ cells (OX6, 3JP, OX17). Treatment with OX8 or OX19 achieved stable reductions of splenic and peripheral blood NK cells and helper/inducer T lymphocytes, respectively, and protected against diabetes. OX19 injections also prevented lymphocytic insulitis, thyroiditis, and the synthesis of autoantibodies to thyroid colloid and smooth muscle antigens. OX8 injections reduced splenic NK-mediated YAC-1 cell lysis, but did not prevent insulitis, thyroiditis, or autoantibody synthesis. Injections of mAb specific for antigens on the surface of helper/inducer cells, and for cells expressing IaE antigens provided marginal protection against diabetes without reductions of phenotypic subsets. These findings suggest that pancreatic beta cell destruction in the spontaneously diabetic BB/Wor rat is mediated by the combined action of NK and helper/inducer cells.

Specific features of T- and NK-cellular immunity in chronic lymphocytic leukemia

2021 ◽  
Vol 66 (6) ◽  
pp. 345-352
Author(s):  
Evgeniy Vladimirovich Pochtar ◽  
S. A. Lugovskaya ◽  
E. V. Naumova ◽  
E. A. Dmitrieva ◽  
A. I. Kostin ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Chronic Lymphocytic Leukemia ◽  
T Lymphocytes ◽  
Nk Cells ◽  
Lymphocytic Leukemia ◽  
Positive Trend ◽  
Functional Changes ◽  
Activated T Lymphocytes ◽  
T Helpers

Profound immunological dysfunction is the key factor determining the development of infectious complications in chronic lymphocytic leukemia (CLL). The aim of this work is to assess the features of the subpopulation composition of T-lymphocytes (T-helpers (Th), cytotoxic T-lymphocytes (Tcyt), T regulatory cells (Treg), T-NK cells, naive Th, Th-memory, activated T-lymphocytes, TCRγδ cells) and NK cells in peripheral blood of patients with newly diagnosed chronic lymphocytic leukemia (CLL) and receiving ibrutinib therapy. Hematological and immunophenotypic studies have been performed in 30 patients with previously untreated CLL, 122 patients on ibrutinib therapy and 20 healthy donors. The subpopulation composition of T-lymphocytes (Th, Tcyt, Treg, T-NK, naive T-helpers, memory T-helpers, TCRγδ cells, activated T-lymphocytes) and NK cells has been assessed on flow cytometer (FACSCanto II (BD)) using the following panel of monoclonal antibodies: CD45, CD19, CD3, CD4, CD5, CD8, TCRγδ, CD127, CD16, CD56, CD57 CD45RA, CD45R0, HLA-DR, CD25. Compared to controls all CLL samples were found to have higher the absolute number of T-lymphocytes, NK cells and their subpopulations, T-helpers (especially of memory T-cells), cytotoxic T-cells, regulatory T-cells, TCRγδ T-cells, activated T-lymphocytes, increased cytotoxic potential of NK cells in previously untreated CLL patients. Patients who received ibrutinib therapy have registered a positive trend towards recovery of the subpopulation composition of T-lymphocytes and NK-cells. CLL patients have been found to have quantitative and functional changes in the subpopulations of T-lymphocytes and NK cells, indicating dysregulation of the immune response, and a high risk of developing infections. Monitoring of immunological parameters for ibrutinib therapy make possible to estimate impact of ibrutinib on the adaptive anti-CLL immune response.

Immature T lymphocytes in human cord blood identified by monoclonal antibodies: A model for the study of the differentiation pathway of T cells in humans

1984 ◽  
Vol 89 (1) ◽  
pp. 194-201 ◽  
Author(s):  
Robert Foa ◽  
Maria Cristina Giubellino ◽  
Maria Teresa Fierro ◽  
Paolo Lusso ◽  
Maria Luisa Ferrando
Keyword(s):  
T Cells ◽  
Monoclonal Antibodies ◽  
T Lymphocytes ◽  
Cord Blood ◽  
Human Cord Blood

Transplantation Of TcRαβ/CD19 Depleted Stem Cells From Haploidentical Donors In Children: Current Results

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 692-692 ◽  
Author(s):  
Peter Lang ◽  
Tobias Feuchtinger ◽  
Heiko-Manuel Teltschik ◽  
Michael Schumm ◽  
Patrick Schlegel ◽  
...  
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
T Lymphocytes ◽  
Nk Cells ◽  
Chronic Gvhd ◽  
Cell Depletion ◽  
T Cell Depletion ◽  
Αβ T Cells

Abstract T-cell depletion of the graft is an effective method to prevent or completely avoid Graft-versus-Host Disease (GvHD) in haploidentical stem cell transplantation. In order to increase the T-cell depletion efficacy while maintaining the anti-tumor and anti-infectious properties of the graft, we have investigated a new T-cell depletion method which removes αβ+ T-lymphocytes via a biotinylated anti-TcRαβ antibody followed by an anti-biotin antibody conjugated to magnetic microbeads while retaining γδ+ T-lymphocytes, Natural killer (NK) cells and other cells in the graft. In addition, CD19+ B-lymphocytes were concomitantly depleted for the prevention of posttransplant EBV-associated lymphoproliferative disease. The CliniMACS system was used for manipulation of peripheral stem cell grafts from full haplotype mismatched family donors in 35 patients. Results The overall depletion of αβ+ T-cells was highly effective with 4.6 log (range 3.8–5.0). Patients received a median number of only 14 x 103/kg residual αβ+ T-cells. Recovery of CD34+ stem cells was 72%, and the median number of infused CD34+ stem cells was 12 x 106/kg (range 5-38 x 106/kg). Additionally, the patients received 2 types of potential antileukemic effector cells: 107 x 106/kg (range 35 -192 x 106/kg) CD56+ NK-cells and 11 x 106/kg (range 5–30 x 106/kg) γδ+ T-lymphocytes. Diagnoses were ALL (n=20), AML/MDS/JMML (n=9), nonmalignant diseases (n=4), solid tumors (n=2); disease status: CR2-CR6 (n=17), active disease (n=18). 23 patients received a second or third SCT (65%). A toxicity reduced conditioning regimen (fludarabin 40mg/m² or clofarabin 50mg/m² (day -8 to d -5), thiotepa 10mg/kg (d -4), melphalan 70mg/m² (d -3 and d -2) was used. The anti CD3 specific OKT3 antibody was used as rejection prophylaxis from day -8 to day -1 without affecting cotransfused effector cells because of its short half-life period in the first 7 patients. However, due to its restricted availability, the substance was substituted since 2011 by a reduced ATG-F dose (15mg/kg) given at start of the conditioning regimen in order not to impair NK and γδ+ T-cells of the grafts (1 mg/kg d -12, 4 mg/kg d -11, 5 mg/kg d -10 and -9; n=28 patients). Short course MMF (until day +30) was given in 25 patients. Graft rejection occurred in 14% of the patients. However, after reconditioning and second stem cell donation, final engraftment was achieved in all patients. The median time to reach neutrophil and platelet recovery in patients with primary engraftment was 10 and 11 days respectively. All patients showed a rapid immune reconstitution with 250 (OKT3 conditioning) and 273 (ATG conditioning) CD3+ T-cells/µl, 30 (OKT3) and 47 (ATG) CD3+4+/µl and 300 (OKT3) and 382 (ATG) CD56+ NK-cells/µl at day +30 posttransplant. γδ+ T-cells started to expand faster than αβ+ T-cells in the early post-transplant period (156 vs. 82 cells/µl at day +30) whereas at day +90, αβ+ T-cells were predominant (170 vs. 134 cells/µl). Acute GvHD grade 0-I occurred in 25 patients (71%); 6 patients had GvHD II (17%), 3 patients had GvHD III (9%) and one patients experienced GvHD grade IV (3%). 3 patients experienced chronic GvHD (8%). Incidence of acute GvHD was not influenced by the number of residual T cells or by the type of serotherapy. 1 year EFS for patients with acute leukemias was 66% (any CR) and 14% (active disease).TRM at 1 year was 20%. Conclusions These data indicate that transplantation of TcR αβ+/CD19 depleted cells from a haploidentical donor results in sustained engraftment, remarkably fast immune reconstitution and low incidence of both acute and chronic GvHD. OKT3 could be substituted by ATG without negative effects. The anti-leukemic efficacy of this approach in comparison to other methods of T-cell depletion needs to be evaluated with a longer patient follow-up. Disclosures: No relevant conflicts of interest to declare.

Improved Immune Recovery after Transplantation of TCRαβ/CD19 Depleted Allografts from Haploidentical Donors in Pediatric Patients

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 852-852
Author(s):  
Peter Lang ◽  
Tobias Feuchtinger ◽  
Heiko-Manuel Teltschik ◽  
Wolfgang Schwinger ◽  
Patrick Schlegel ◽  
...  
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
T Lymphocytes ◽  
Nk Cells ◽  
Pediatric Patients ◽  
Conflicts Of Interest ◽  
Γδ T Cells ◽  
Control Group ◽  
Unrelated Donor ◽  
Immune Recovery

Abstract Transplantation of haploidentical stem cells has become an accepted option for pediatric patients and adults with high risk malignancies who lack a matched related or unrelated donor. In recent years, the majority of pediatric transplant centers chose the CD34 positive selection of peripheral stem cells, which allowed minimizing GvHD by effective reduction of T cells in the graft. However, infectious complications caused by delayed immune recovery were a major reason for transplant related mortality (TRM). In order to improve the immune recovery, we have established a new T-cell depletion method which removes αβ+ T-lymphocytes via a biotinylated anti-TcRαβ antibody followed by an anti-biotin antibody conjugated to magnetic microbeads while retaining γδ+ T-lymphocytes, natural killer (NK) cells and other cells in the graft. In addition, CD19+ B-lymphocytes were concomitantly depleted for the prevention of post-transplant EBV-associated lymphoproliferative disease. Immune recovery was retrospectively analyzed in a cohort of 41 patients with acute leukemia, MDS and non-malignant diseases, who received αβ T and B cell depleted allografts from haploidentical family donors. Conditioning regimens consisted of fludarabine or clofarabine, thiotepa, melphalan and serotherapy with OKT3 or ATG-Fresenius®. Graft manipulation was carried out with anti TCRαβ and anti CD19 antibodies and immunomagnetic microbeads. γδ T cells and NK cells remained in the grafts. Primary engraftment occurred in 88%, acute graft versus host disease (aGvHD) grade II and III-IV occurred in 10% and 15%. Immune recovery data were available in 26 patients and comparable after OKT3 (n=7) or ATG-F® (n=19). Median time to reach > 100 CD3+/µl, > 200 CD19+ cells/µl and > 200 CD56+ cells/µl for the whole group was 13, 127 and 12.5 days. Compared to a historical control group of patients with CD34 positive selected grafts, significantly higher cell numbers were found for CD3+ at days +30 and +90 (267 vs. 27 and 397 vs. 163 cells/µl), for CD3+4+ at day +30 (58 vs. 11 cells/µl) and for CD56+ at day +14 (622 vs. 27 cells/µl). The clinical impact of this accelerated immune recovery will be evaluated in an ongoing prospective multi-center trial. Disclosures No relevant conflicts of interest to declare.

scholarly journals Dendritic cells matured with recombinant human sperm associated antigen 9 (rhSPAG9) induce CD4+, CD8+ T cells and activate NK cells: A potential candidate molecule for immunotherapy in cervical cancer

2020 ◽  
Author(s):  
Hemavathi Dhandapani ◽  
Hascitha Jayakumar ◽  
Abirami Seetharaman ◽  
Selvaluxmy Ganeshrajah ◽  
Shirley Sunder Singh ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
T Cells ◽  
T Lymphocytes ◽  
Nk Cells ◽  
Cytotoxic T Lymphocytes ◽  
Cd8 T Cells ◽  
Functional Characterization ◽  
Potential Candidate ◽  
Autologous Tumour ◽  
Antigenic Source

Abstract Background Dendritic cell (DC)-based immunotherapy is capable of activating the immune system, and in particular tumour-specific cytotoxic T lymphocytes (CTLs) to eradicate the tumour. However, major limitations are the availability of autologous tumour cells as antigenic source and the selection of antigen that may have potential to activate both CD8 + and CD4 + T cells in immune-specific manner. Recently, we reported the expression of sperm associated antigen 9 (SPAG9) that is associated with various types of malignancies including cervical cancer. We examined the recombinant human SPAG9 (rhSPAG9) as an antigenic source for generating efficient DCs to stimulate CD4 + and CD8 + T cell responses for future DCs-based vaccine trials in cervical cancer patients. Methods Human monocytes derived DCs were pulsed with different concentrations (250 ng/ml to 1000 ng/ml) of recombinant human SPAG9 (rhSPAG9) and evaluated for their phenotypic and functional ability. Subsequently, the efficacy of DCs primed with 750 ng/ml of rhSPAG9 (SPDCs) was compared with DCs primed with autologous tumour lysate (TLDCs), to induce CD4+, CD8 + T cells and activating NK cells. In addition, we investigated the effect of the chemotherapeutic drug cisplatin on phenotypic and functional potential of SPDCs. Results Phenotypic and functional characterization of DCs pulsed with 750 ng/ml rhSPAG9 was found to be optimal and effective for priming DCs. SPDCs were also capable of stimulating allogeneic CD4 + and CD8 + T cells similar to TLDCs. SPDCs showed a statistically insignificant increase in the expression of maturation marker CD83 and migration towards CCL19 and CCL21 compared with TLDCs (CD83 p = 0.4; for migration p = 0.2). In contrast, TLDCs showed better proliferation and secretion of Th1 cytokines (IL12p40, IL12p70 and IFNγ) compared to SPDCs, but this was also not statistically significant (IL12p40, p = 0.06). We also found that clinical dose of cisplatin (200 µM) treated SPDCs were able to stimulate the proliferation of cytotoxic T lymphocytes without increasing the FOXP3+Tregs in autologous co-cultures. Conclusions This is the first report to suggest that rhSPAG9 is an effective antigen for pulsing DCs that are capable of eliciting a potent Th1 response which, in turn, may help in decreasing the tumour burden when used along with a cisplatin based combinatorial regimen for therapeutic intervention. This strategy provides an insight to consider rhSPAG9 as a strong immunogen for DC-based immunotherapy for cervical cancer.

scholarly journals Dendritic cells matured with recombinant human sperm associated antigen 9 (rhSPAG9) induce CD4+, CD8+ T cells and activate NK cells: a potential candidate molecule for immunotherapy in cervical cancer

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Hemavathi Dhandapani ◽  
Hascitha Jayakumar ◽  
Abirami Seetharaman ◽  
Shirley Sunder Singh ◽  
Selvaluxmy Ganeshrajah ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
T Cells ◽  
T Lymphocytes ◽  
Nk Cells ◽  
Tumor Cells ◽  
Cytotoxic T Lymphocytes ◽  
Functional Characterization ◽  
Autologous Tumor ◽  
Potential Candidate ◽  
Antigenic Source

Abstract Background Dendritic cell (DC)-based immunotherapy is capable of activating the immune system and in particular tumor-specific cytotoxic T lymphocytes (CTLs) to eradicate the tumor. However, major limitations are the availability of autologous tumor cells as antigenic source and the selection of antigen that may have potential to activate both CD4+ and CD8+ T cells in immune-specific manner. Recently, we reported the expression of sperm associated antigen 9 (SPAG9) that is associated with various types of malignancies including cervical cancer. We examined the recombinant human SPAG9 (rhSPAG9) as an antigenic source for generating efficient DCs to stimulate CD4+ and CD8+ T cell responses for future DCs-based vaccine trials in cervical cancer patients. Methods Human monocytes derived DCs were pulsed with different concentrations (250 ng/ml to 1000 ng/ml) of recombinant human SPAG9 (rhSPAG9) and evaluated for their phenotypic and functional ability. The efficacy of DCs primed with 750 ng/ml of rhSPAG9 (SPDCs) was compared with DCs primed with autologous tumor lysates (TLDCs), to induce CD4+, CD8+ T cells and activating NK cells. In addition, we investigated the effect of the chemotherapeutic drug cisplatin on phenotypic and functional potential of SPDCs. Results Phenotypic and functional characterization of DCs pulsed with 750 ng/ml rhSPAG9 was found to be optimal and effective for priming DCs. SPDCs were also capable of stimulating allogeneic T cells similar to TLDCs. SPDCs showed a statistically insignificant increase in the expression of maturation marker CD83 and migration towards CCL19 and CCL21 compared with TLDCs (CD83; P = 0.4; migration; P = 0.2). In contrast, although TLDCs showed better proliferation and secretion of Th1 cytokines (IL12p40, IL12p70 and IFNγ) compared to SPDCs, this difference was not statistically significant (IL12p40, P = 0.06). Further we also observed that clinical dose of cisplatin (200 µM) treated SPDCs were able to stimulate the proliferation of cytotoxic T lymphocytes without increasing the FOXP3+ Tregs in autologous co-cultures. Conclusions In summary, in order to overcome the limitation of the availability of autologous tumor cells as antigenic sources, our present strategy provides an insight to consider rhSPAG9 as a strong immunogen for DC-based immunotherapy for cervical cancer trials and warrants further studies. This is the first report to suggest that rhSPAG9 is an effective antigen for pulsing DCs that are capable of eliciting a potent Th1 response which, in turn, may help in decreasing the tumor burden when used along with a cisplatin based combinatorial regimen for therapeutic intervention.

scholarly journals Activation of rat T lymphocytes by anti-CD2 monoclonal antibodies.

1988 ◽  
Vol 167 (6) ◽  
pp. 1861-1872 ◽  
Author(s):  
S J Clark ◽  
D A Law ◽  
D J Paterson ◽  
M Puklavec ◽  
A F Williams
Keyword(s):  
T Cells ◽  
Monoclonal Antibodies ◽  
T Cell ◽  
T Lymphocytes ◽  
Phorbol Ester ◽  
Mitogenic Effect ◽  
Accessory Cells ◽  
Reverse Situation

Rat T cells and thymocytes were induced to proliferate by a pair of mAbs, MRC OX-54 and MRC OX-55, directed against rat CD2. Accessory cells were required but their role was not simply for crosslinking of the two mAbs, as neither MRC OX-54 nor MRC OX-55 alone, in the presence of a crosslinking second antibody, caused T cell mitogenesis. Nor could the phorbol ester PMA replace either antibody. The two mAbs recognized distinct epitopes on rat CD2; however, MRC OX-54 could partially block MRC OX-55 binding whereas the reverse situation was not seen. A further CD2 epitope was recognized by two mutually competitive mAbs, MRC OX-34 and MRC OX-53, which were not mitogenic. Neither MRC OX-34 nor MRC OX-53 affected the binding of MRC OX-54 or MRC OX-55, yet they prevented the mitogenic effect induced by these mAbs. The presence of mAbs against CD4 and the IL-2-R also abrogated this mitogenesis, whereas an anti-CD5 mAb augmented the CD2-induced proliferation.

A Novel Method for Propagating Primary Natural Killer (NK) Cells Allows Highly Efficient Expression of Anti-CD19 Chimeric Receptors and Generation of Powerful Cytotoxicity Against NK-Resistant Acute Lymphoblastic Leukemia Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 306-306
Author(s):  
Chihaya Imai ◽  
Shotaro Iwamoto ◽  
Dario Campana
Keyword(s):  
T Cells ◽  
Acute Lymphoblastic Leukemia ◽  
T Lymphocytes ◽  
Nk Cells ◽  
Treatment Option ◽  
Nk Cell ◽  
Lymphoblastic Leukemia ◽  
Chimeric Receptors ◽  
Membrane Bound

Abstract Despite intensive chemotherapy, acute lymphoblastic leukemia (ALL) recurs in approximately 20% of children and 65% of adults. For most of these patients, allogeneic hematopoietic cell transplantation (HCT) is the only curative treatment option but risk of relapse after transplantation is high. Donor lymphocyte infusions can suppress leukemia relapse but they are generally ineffective in ALL. We and others have shown that T lymphocytes transduced with anti-CD19 chimeric receptors have remarkable anti-ALL capacity in vitro and in vivo, suggesting the clinical testing of receptor-modified autologous T cells in patients with persistent minimal residual disease. However, the use of allogeneic receptor-modified T lymphocytes after HCT might carry the risk of severe graft-versus-host disease (GvHD). In this setting, the use of CD3-negative NK cells is attractive because they should not cause GvHD. Spontaneous cytotoxicity of NK cells against ALL is weak, if measurable at all. To test whether anti-CD19 chimeric receptors could enhance it, we developed a method to specifically expand human primary NK cells and induce high levels of receptor expression. Specific NK cell expansion has been problematic to achieve with established methods, because CD3+ T cells expand preferentially; even with T-cell depletion, residual T cells typically become prominent after stimulation. We overcame this obstacle by generating a genetically-modified K562 myeloid leukemia cell line that expresses membrane-bound interleukin-15 (IL-15) and 4-1BB ligand (CD137L) (K562-mb15-137L). Peripheral blood mononuclear cells from 8 donors were cultured with K562-mb15-137L in the presence of 10 IU/mL IL-2. After 1 week of culture with K562-mb15-137L, CD3- CD56+ NK cells expanded by 16.3 ± 5.9 fold, whereas CD3+ T cells did not expand. The stimulatory effect of K562-mb15-137L was much higher than that of K562 cells transduced with control vectors, K562 expressing membrane-bound IL-15 or CD137L alone, or K562 expressing wild-type IL-15 instead of membrane-bound IL-15. NK cell exposed to K562-mb15-137L were transduced with a retroviral vector and the anti-CD19-BB-ζ receptor, consisting of the single-chain variable domain of an anti-CD19 monoclonal antibody, the hinge and transmembrane domains of CD8α, and the signaling domains of CD3ζ and 4-1BB. 4-1BB mediates signals that are crucial for immune response to tumors in vivo and significantly improves chimeric receptor signaling. In 27 experiments, mean (± SD) transduction efficiency after 7–14 days was 67.5% ± 16.7%. Seven days after transduction, 92.3% (range 84.7%–99.4%) of cells were CD3- CD56+ NK cells; expression of receptors on the cell surface was high. NK cells expressing anti-CD19-BB-ζ had powerful cytotoxicity against NK-resistant B-lineage ALL cell lines and primary ALL cells. NK cells transduced with anti-CD19-BB-ζ had consistently higher cytotoxicity than those transduced with receptors lacking 4-1BB. The method described here allows specific expansion of primary NK cells and highly efficient transduction of chimeric receptors. Expression of anti-CD19-BB-ζ receptors in NK cells markedly enhances their anti-ALL activity. This approach could be a valuable treatment option for patients with refractory or relapsed B-cell malignancies after HCT.

Impaired Maturation and Survival of T Lymphocytes, B Lymphocytes, and NK Cells in Mice Lacking Gimap5/Ian5.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 921-921
Author(s):  
Ryan D. Schulteis ◽  
Xuezhi Dai ◽  
Haiyan Chu ◽  
Brandon Edwards ◽  
Dipica Haribhai ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Nk Cells ◽  
B Lymphocytes ◽  
Fold Reduction ◽  
Autoimmune Pathology ◽  
T Cell Lymphopenia ◽  
Cell Commitment ◽  
T Cell Survival

Abstract In biobreeding rats (BB), the lyp mutation in Gimap5/Ian5 is associated with T-cell lymphopenia and autoimmune insulinitis. To delineate the role of Gimap5 in peripheral T cell survival, we generated Gimap5-deficient mice by targeted disruption. Gimap5−/− mice are viable to adulthood, but develop fulminant autoimmune hepatitis, become moribund, and die at a median age of 12 weeks. Gimap5−/− mice are lymphopenic, displaying an overall 7-fold reduction in peripheral T cells and a 43-fold reduction in peripheral CD8+ T cells. Additionally, Gimap5−/− mice exhibit an early, complete block in both NK and NKT lineage development and a partial block in B cell commitment to T1, T2, and mature subsets. Data from lethally irradiated congenic strains reconstituted with Gimap5−/− bone marrow will also be presented. Taken together, these data indicate that Gimap5 is necessary for peripheral survival of T lymphocytes and development of B lymphocytes and NK cells. Furthermore, these data suggest that Gimap5 deficiency plays a role in the development of autoimmune pathology in the mouse.

Sign in / Sign up

Export Citation Format

Share Document