| 1. |
- Sherina, Natalia, et al.
(författare)
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Persistence of SARS-CoV-2-specific B and T cell responses in convalescent COVID-19 patients 6-8 months after the infection
- 2021
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Ingår i: Med. - : Elsevier BV. - 2666-6340. ; 2:3, s. 281-295
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Tidskriftsartikel (refereegranskat)abstract
- Background: Monitoring the adaptive immune responses during the natural course of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection provides useful information for the development of vaccination strategies against this virus and its emerging variants. We thus profiled the serum anti-SARS-CoV-2 antibody (Ab) levels and specific memory B and T cell responses in convalescent coronavirus disease 2019 (COVID-19) patients.Methods: A total of 119 samples from 88 convalescent donors who experienced mild to critical disease were tested for the presence of elevated anti-spike and anti-receptor binding domain Ab levels over a period of 8 months. In addition, the levels of SARS-CoV-2 neutralizing Abs and specific memory B and T cell responses were tested in a subset of samples.Findings: Anti-SARS-CoV-2 Abs were present in 85% of the samples collected within 4 weeks after the onset of symptoms in COVID-19 patients. Levels of specific immunoglobulin M (IgM)/IgA Abs declined after 1 month, while levels of specific IgG Abs and plasma neutralizing activities remained relatively stable up to 6 months after diagnosis. Anti-SARS-CoV-2 IgG Abs were still present, although at a significantly lower level, in 80% of the samples collected at 6-8 months after symptom onset. SARS-CoV-2-specific memory B and T cell responses developed with time and were persistent in all of the patients followed up for 6-8 months.Conclusions: Our data suggest that protective adaptive immunity following natural infection of SARS-CoV-2 may persist for at least 6-8 months, regardless of disease severity. Development of medium- or long-term protective immunity through vaccination may thus be possible.
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| 2. |
- Blixt, Ola, et al.
(författare)
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Anticarbohydrate antibody repertoires in patients transplanted with fetal pig islets revealed by glycan arrays
- 2009
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Ingår i: American Journal of Transplantation. - 1600-6135 .- 1600-6143. ; 9, s. 83-90
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Tidskriftsartikel (refereegranskat)abstract
- Ten patients with type I diabetes were transplanted with porcine fetal islet-like cell clusters (ICC) between 1990 and 1993. A significant rise in the anti-a -Gal antibody titers was seen posttransplant, but also nona -Gal-specific antibodies were detected in some patients. We have reanalyzed the carbohydrate specificity of antibodies in the sera from seven of these patients taken before transplantation, 1, 6 and 12 months posttransplantation using a glycan array with 200 structurally defined glycans. The main findings were: (i) prepig ICC transplantation patients had antibodies reactive with terminal a -GalNAc (e.g. the Forssman antigen, but not the blood group A determinant in blood group A patients), a -Gal (except blood group B determinants in B individuals), b 3-linked Gal especially Galb 1,3GlcNAc even if terminally sulfated or sialylated, b -GlcNAc except if b 1,3-linked and oligomannosyl compounds; (ii) the titers of all carbohydrate-specific antibodies detected before transplantation rose after transplantation; (iii) the kinetics of the antibody responses differed between patients; (iv) in some patients antibodies reacting with Gala 1,3Lex and several structures terminated with Neu5Gc appeared after transplantation. In conclusion, anti-a -Gal antibodies are the predominant anticarbohydrate antibodies detected after porcine ICC transplantation, with some patients also developing Neu5Gc-specific antibodies. Their clinical significance needs to be established.
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| 3. |
- Diab, Randa A H, et al.
(författare)
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Rat islets are not rejected by anti-islet antibodies in mice treated with costimulation blockade.
- 2014
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Ingår i: Xenotransplantation. - : Wiley. - 1399-3089 .- 0908-665X. ; 21:4, s. 353-66
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Tidskriftsartikel (refereegranskat)abstract
- Costimulation blockade can prevent rejection of islet xenografts in naïve but not sensitized recipients. Donor-specific antibodies (DSA) may partly explain this observation. The effect of DSA on rat islet xenograft survival in mice receiving costimulation blockade was investigated.
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| 4. |
- Grinnemo, Karl-Henrik, et al.
(författare)
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Costimulation blockade induces tolerance to HESC transplanted to the testis and induces regulatory T-cells to HESC transplanted into the heart
- 2008
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Ingår i: Stem Cells. - : Oxford University Press (OUP). - 1549-4918 .- 1066-5099. ; 26:7, s. 1850-1857
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Tidskriftsartikel (refereegranskat)abstract
- In order to study the ability of costimulation blockade to induce tolerance to human embryonic stem cells (HESC), severe combined immunodeficient (SCID), and immunocompetent C57BL/6 mice treated with costimulation blockade received intratesticular and intramyocardial HESC transplants. All SCID mice with intratesticular HESC transplants developed teratoma. When SCID mice were transplanted intramyocardially, only two of five mice developed teratoma-like tumors. C57BL/6 mice transplanted intratesticularly and treated with costimulation blockade all developed teratoma and were surrounded by CD4(+)CD25(+)Foxp3(+) T-cells, while isotype control treated recipients rejected their grafts. Most C57BL/6 mice transplanted intramyocardially and treated with costimulation blockade demonstrated lymphocytic infiltrates 1 month after transplantation, whereas one maintained its graft. Isolation of regulatory T-cells from intramyocardial transplanted recipients treated with costimulation blockade demonstrated specificity toward undifferentiated HESC and down-regulated naive T-cell activation toward HESC. These results demonstrate that costimulation blockade is sufficiently robust to induce tolerance to HESC in the immune-privileged environment of the testis. HESC specific regulatory T-cells developed to HESC transplanted to the heart and the success of transplantation was similar to that seen in SCID mice.
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| 5. |
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| 6. |
- Jia, Xiaohui, et al.
(författare)
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Exendin-4 Increases the Expression of Hypoxia-InducibleFactor-1 in Rat Islets and Preserves the Endocrine CellVolume of Both Free and Macroencapsulated Islet Grafts
- 2012
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Ingår i: Cell Transplantation. - 0963-6897. ; 21:6, s. 1269-1283
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Tidskriftsartikel (refereegranskat)abstract
- In this study, we evaluated the effects of exendin-4 on free and encapsulated islet grafts in a rodent model.We also investigated the role of a transcription factor, hypoxia-inducible factor-1 (HIF-1), in mediating thebeneficial effects of exendin-4. Diabetic athymic mice were transplanted with free rat islets under the kidneycapsule or with macroencapsulated rat islets SC with or without exendin-4, islet preculture (exendin-4 0.1nM for 20 h), and/or recipient treatment (IP 100 ng/day, day 0–7). The mice were followed for 4 weeks andthe graft function andβ-cell volume were evaluated. The effects of exendin-4 on islet HIF-1α mRNAand protein expression and on ATP content in a rat insulinoma cell line (INS-1E) were also examined.Preculture with exendin-4 followed by recipient treatment improved the outcome of both free (73% graftfunction vs. 26% in controls,p = 0.03) and macroencapsulated islet grafts (100% vs. 25% in controls, p =0.02). In macroencapsulated grafts, the exendin-4-treated group had significantly larger endocrine volume,less graft necrosis, and more blood vessels around the capsule. In rat islets cultured with exendin-4, HIF-1αmRNA and protein expression were significantly enhanced. ATP content was increased in exendin-4-treatedINS-1E cells under hypoxic conditions. The improved functional outcome after transplantation of a marginalislet mass with a brief initial treatment with exendin-4 is related to a larger surviving endocrine cell volume.Exendin-4 may improve islet graft resistance to hypoxia during the peritransplant period by increasing theexpression of HIF-1
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| 7. |
- Kumagai-Braesch, Makiko, et al.
(författare)
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Anti-LFA-1 Improves Pig Islet Xenograft Function in Diabetic Mice When Long-Term Acceptance Is Induced by CTLA4Ig/Anti-CD40L.
- 2007
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Ingår i: Transplantation. - : Ovid Technologies (Wolters Kluwer Health). - 1534-6080 .- 0041-1337. ; 83:9, s. 1259-1267
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Tidskriftsartikel (refereegranskat)abstract
- Background. It has been previously demonstrated that addition of anti-LFA-1 to a combination of CTLA4Ig and anti-CD40L induces the permanent acceptance of dopaminergic fetal pig xenografts when transplanted into the brain of wild-type mice. The purpose of this study was to test whether this costimulation blockade also can induce acceptance of adult pig islets transplanted to C5713L/6 mice with streptozotocin-induced diabetes. Methods. Recipients were treated with CTLA4Ig/anti-CD40L +/- anti-LFA-1 or isotype control antibodies during the first week after transplantation. Half of the costimulation blockade-treated recipients had their grafts removed after 8 weeks. The other half was observed up to 5 months. Results. Recipients treated with CTLA4Ig/anti-CD40L/anti-LFA-1 had significantly lower blood glucose and gained more weight than CTLA4Ig/anti-CD40L-treated recipients. CTLA4Ig/anti-CD40L-treated recipients exhibited unstable blood glucose. IPGTT of these recipients revealed a slow recovery to normal blood glucose levels at week 4. In comparison, CTLA4Ig/anti-CD40L/anti-LFA-1 treated recipients exhibited a significantly superior glucose clearance. CTLA4Ig/anti-CD40L +/- anti-LFA-1 treated recipients did not produce anti-pig IgG, whereas control antibody-treated mice did. CD4+ T cells from costimulation blockade-treated recipients proliferated less than CD4+ T cells from control antibody-treated mice when co-cultured with syngeneic antigen presenting cells loaded with pig islet antigens. Conclusions. CTLA4Ig/anti-CD40L/anti-LFA-1-treated recipients had superior islet function compared with CTLA4Ig/anti-CD40L-treated recipients. However, both costimulation blockade regimens led to islet graft acceptance up to 5 months after a 1-week treatment.
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| 8. |
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| 9. |
- Kumagai-Braesch, Makiko
(författare)
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Immunological characterisation of human anti-pig responses in vitro
- 1998
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Xenotransplantation of organs or cells might solve the current problems of organ shortage. However, several problems need to be solved before xenotransplantation can become a successful clinical practice. Ethical, physiological, microbiological and immunological barriers need to be overcome. Presently, efforts are concentrated to providing porcine organs or cells for transplantation. This is mainly due to ethical and microbiological barriers that prevent the use of primates as donors for clinical transplantation. But pig to human transplantation is discordant, since human beings have natural antibodies against pig cells, which mediate hyperacute rejection of vascularised grafts. Therefore initial xenotransplantation trials to use xenogeneic cells for transplantation has been performed, since such cells might be insensitive to the detrimental effects of preformed natural antibodies. In this thesis, we have characterised human natural antibody reactivity against pig cells in vitro, with special reference to porcine islet-like cells. We have also characterised the cellular immune response activated directly by porcine xenogeneic stimulator cells or indirectly by porcine peptides presented by human antigen presenting cells. Xenogeneic natural human antibodies against porcine cells were mainly of IgM, IgG2 and IgA subclasses. Only 30% of all samples tested contained IgG3 antibodies, capable of mediating antibody dependent cellular cytotoxicity (ADCC) of pig Iymphoid cells. In vitro cultured fetal porcine islet cells were insensitive to the cytotoxic effects of natural antibodies as well as to ADCC effects. This finding was a prerequisite for the clinical trial. A characterisation of the cellular human anti-pig response was carried out in vitro, evaluating both the direct pathway of activation by porcine stimulator cells as well as the indirect pathway mediated by porcine peptides presented by human responder antigen presenting cells. Direct xenoactivation of CD4+ T cells led to proliferation, expression of functional IL-2 receptors and cytokine production with de novo synthesis of IL-2 and IFN-y in magnitude and character comparable to that induced by allogeneic stimulator cells. CD8+ T cells were less efficiently stimulated directly. The frequency of xenoreactive proliferating as well as of cytotoxic precursor cells was approximately 10 x lower than in the allogeneic combination. Indirect xenoactivation resulted preferentially in proliferation and CD25 expression in the CD4+ T cell population. Xenostimulation by porcine Iymphocytes in vitro led to the formation of both MHC-restricted cytotoxic T cells as well as to an increase in non-MHC restricted natural killer (NK) cells. In vitro activation of purified human NK cells was strictly dependent on human IL-2. Fetal porcine islet like cells were insensitive to resting human NK cells but sensitive to in vitro activated NK cells. Ten diabetic patients received fetal porcine xenogeneic islet cells. All patients promptly synthesised high levels of IgM and IgG antibodies reactive against pig cells, which reached a peak at 30-50 days. The humoral immune response included IgGI and IgG3 antibodies, indicative of a class switch. Xenoimmune antibodies mediate ADCC against pig blood mononuclear cells, fibroblasts as well as fetal porcine islet-like cells. Specificity determinations of xenoimmune antibodies have been performed with alpha-1,3-galactosyltransferase transfected Raji cells expressing Gal-alpha-1,3-Gal epitopes. The results indicated that xenoimmune antibodies were directed against Gal-alpha-1,3-Gal epitopes on target cells.
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| 10. |
- Marcotte, Harold, et al.
(författare)
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Conversion of monoclonal IgG to dimeric and secretory IgA restores neutralizing ability and prevents Infection of Omicron lineages
- 2024
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : NATL ACAD SCIENCES. - 0027-8424 .- 1091-6490. ; 121:3
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Tidskriftsartikel (refereegranskat)abstract
- The emergence of Omicron lineages and descendent subvariants continues to present a severe threat to the effectiveness of vaccines and therapeutic antibodies. We have previ- ously suggested that an insufficient mucosal immunoglobulin A (IgA) response induced by the mRNA vaccines is associated with a surge in breakthrough infections. Here, we further show that the intramuscular mRNA and/or inactivated vaccines cannot suffi- ciently boost the mucosal secretory IgA response in uninfected individuals, particu- larly against the Omicron variant. We thus engineered and characterized recombinant monomeric, dimeric, and secretory IgAl antibodies derived from four neutralizing IgG monoclonal antibodies (mAbs 01A05, rmAb23, DXP-604, and XG014) targeting the receptor-binding domain of the spike protein. Compared to their parental IgG antibod- ies, dimeric and secretory IgAl antibodies showed a higher neutralizing activity against different variants of concern (VOCs), in part due to an increased avidity. Importantly, the dimeric or secretory IgAl form of the DXP-604 antibody significantly outperformed its parental IgG antibody, and neutralized the Omicron lineages BA.1, BA.2, and BA.4/5 with a 25- to 75-fold increase in potency. In human angiotensin converting enzyme 2 (ACE2) transgenic mice, a single intranasal dose of the dimeric IgA DXP-604 conferred prophylactic and therapeutic protection against Omicron BA.5. Thus, dimeric or secre- tory IgA delivered by nasal administration may potentially be exploited for the treatment Iand prevention of Omicron infection, thereby providing an alternative tool for combating immune evasion by the current circulating subvariants and, potentially, future VOCs.
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| 11. |
- Takahashi, Tohru, et al.
(författare)
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Multipotent mesenchymal stromal cells synergize with costimulation blockade in the inhibition of immune responses and the induction of foxp3+ regulatory T cells.
- 2014
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Ingår i: Stem cells translational medicine. - : Oxford University Press (OUP). - 2157-6564 .- 2157-6580. ; 3:12, s. 1484-94
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Tidskriftsartikel (refereegranskat)abstract
- Multipotent mesenchymal stromal cell (MSC) therapy and costimulation blockade are two immunomodulatory strategies being developed concomitantly for the treatment of immunological diseases. Both of these strategies have the capacity to inhibit immune responses and induce regulatory T cells; however, their ability to synergize remains largely unexplored. In order to study this, MSCs from C57BL/6 (H2(b)) mice were infused together with fully major histocompatibility complex-mismatched Balb/c (H2(d)) allogeneic islets into the portal vein of diabetic C57BL/6 (H2(b)) mice, which were subsequently treated with costimulation blockade for the first 10 days after transplantation. Mice receiving both recipient-type MSCs, CTLA4Ig, and anti-CD40L demonstrated indefinite graft acceptance, just as did most of the recipients receiving MSCs and CTLA4Ig. Recipients of MSCs only rejected their grafts, and fewer than one half of the recipients treated with costimulation blockade alone achieved permanent engraftment. The livers of the recipients treated with MSCs plus costimulation blockade contained large numbers of islets surrounded by Foxp3(+) regulatory T cells. These recipients showed reduced antidonor IgG levels and a glucose tolerance similar to that of naïve nondiabetic mice. Intrahepatic lymphocytes and splenocytes from these recipients displayed reduced proliferation and interferon-γ production when re-exposed to donor antigen. MSCs in the presence of costimulation blockade prevented dendritic cell maturation, inhibited T cell proliferation, increased Foxp3(+) regulatory T cell numbers, and increased indoleamine 2,3-dioxygenase activity. These results indicate that MSC infusion and costimulation blockade have complementary immune-modulating effects that can be used for a broad number of applications in transplantation, autoimmunity, and regenerative medicine.
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| 12. |
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| 13. |
- Watanabe, M., et al.
(författare)
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Ex Vivo Generation of Donor Antigen-Specific Immunomodulatory Cells A Comparison Study of Anti-CD80/86 mAbs and CTLA4-lg Costimulatory Blockade
- 2018
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Ingår i: Cell Transplantation. - : SAGE Publications. - 0963-6897 .- 1555-3892. ; 27:11, s. 1692-1704
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Tidskriftsartikel (refereegranskat)abstract
- Adoptive transfer of alloantigen-specific immunomodulatory cells generated ex vivo with anti-CD80/CD86 mAbs (2D10.4/IT2.2) holds promise for operational tolerance after transplantation. However, good manufacturing practice is required to allow widespread clinical application. Belatacept, a clinically approved cytotoxic T-lymphocyte antigen 4-immunoglobulin that also binds CD80/CD86, could be an alternative agent for 2D10.4/IT2.2. With the goal of generating an optimal cell treatment with clinically approved reagents, we evaluated the donor-specific immunomodulatory effects of belatacept- and 2D10.4/IT2.2-generated immunomodulatory cells. Immunomodulatory cells were generated by coculturing responder human peripheral blood mononuclear cells (PBMCs) (50 x 10(6) cells) with irradiated donor PBMCs (20 x 10(6) cells) from eight human leukocyte antigen-mismatched responder-donor pairs in the presence of either 2D10.4/IT2.2 (3 mu g/10(6) cells) or belatacept (40 mu g/10(6) cells). After 14 days of coculture, the frequencies of CD4(+) T cells, CD8(+) T cells, and natural killer cells as well as interferon gamma (IFN-gamma) production in the 2D10.4/IT2.2- and belatacept-treated groups were lower than those in the control group. The percentage of CD19(+) B cells was higher in the 2D10.4/IT2.2- and belatacept-treated groups than in the control group. The frequency of CD4(+)CD25(+)CD127(low)FOXP3(+) T cells increased from 4.1 +/- 1.0% (preculture) to 7.1 +/- 2.6% and 7.3 +/- 2.6% (day 14) in the 2D10.4/IT2.2- and belatacept-treated groups, respectively (p<0.05). Concurrently, delta-2 FOXP3 mRNA expression increased significantly. Compared with cells derived from the no-antibody treated control group, cells generated from both the 2D10.4/IT2.2- and belatacept-treated groups produced lower IFN-gamma and higher interleukin-10 levels in response to donor-antigens, as detected by enzyme-linked immunospot. Most importantly, 2D10.4/IT2.2- and belatacept-generated cells effectively impeded the proliferative responses of freshly isolated responder PBMCs against donor-antigens. Our results indicate that belatacept-generated donor-specific immunomodulatory cells possess comparable phenotypes and immunomodulatory efficacies to those generated with 2D10.4/IT2.2. We suggest that belatacept could be used for ex vivo generation of clinical grade alloantigen-specific immunomodulatory cells for tolerance induction after transplantation.
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| 14. |
- Zuo, Fanglei, et al.
(författare)
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Heterologous immunization with inactivated vaccine followed by mRNA-booster elicits strong immunity against SARS-CoV-2 Omicron variant
- 2022
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- The recent emergence of the Omicron variant has raised concerns on vaccine efficacy and the urgent need to study more efficient vaccination strategies. Here we observed that an mRNA vaccine booster in individuals vaccinated with two doses of inactivated vaccine significantly increased the plasma level of specific antibodies that bind to the receptor-binding domain (RBD) or the spike (S) ectodomain (S1 + S2) of both the G614 and the Omicron variants, compared to two doses of homologous inactivated vaccine. The level of RBD- and S-specific IgG antibodies and virus neutralization titers against variants of concern in the heterologous vaccination group were similar to that in individuals receiving three doses of homologous mRNA-vaccine or a boost of mRNA vaccine after infection, but markedly higher than that in individuals receiving three doses of a homologous inactivated vaccine. This heterologous vaccination regime furthermore significantly enhanced the RBD-specific memory B cell response and S1-specific T cell response, compared to two or three doses of homologous inactivated vaccine. Our study demonstrates that mRNA vaccine booster in individuals vaccinated with inactivated vaccines can be highly beneficial, as it markedly increases the humoral and cellular immune responses against the virus, including the Omicron variant.
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