Allo-HLA reactivity of virus-specific memory T cells is common

Amir, Avital L.; D’Orsogna, Lloyd; Roelen, Dave L.; Loenen, Marleen M. van; Hagedoorn, Renate S.; Boer, Renate de; Hoorn, Menno A.W.G. van der; Kester, Michel G.D.; Doxiadis, Ilias I.N.; Falkenburg, J.H. Frederik; Claas, Frans H.J.; Heemskerk, Mirjam H.M.

doi:10.1182/blood-2009-07-234906

Cited by 267 publications

(313 citation statements)

References 43 publications

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“…Presensitization would be a particular problem if pathogen-specific T cells with cross-reactivity to alloantigens are triggered by encounter with infectious agents. 16,17 Nevertheless, reduced GVHD rates after CD8-depleted DLIs 3 and absent HLA-class-II expression on non-hematopoietic cells under non-inflammatory conditions 18 suggest that CD45RA depletion, albeit less effective in CD4 þ T cells, may decrease the overall GVHD potential of donor leukocytes in vivo.…”

Section: Discussionmentioning

confidence: 99%

Depletion of naive T cells using clinical grade magnetic CD45RA beads: a new approach for GVHD prophylaxis

Teschner

Distler

Wehler

et al. 2013

Bone Marrow Transplant

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Depletion of naive T cells from donor leukapheresis products (LPs) aims at the reduction of alloreactivity, while preserving memory T-cell reactivity (for example, to pathogens). This study established the immunomagnetic depletion procedure under clean room conditions using CD45RA beads and analyzed LPs of six donors for cell composition and functional immune responses. CD45RA depletion resulted in 3.4-4.7 log (median 4.4) reduction of CD45RA þ T cells, thereby eliminating naive and late effector T cells. B cells were also completely removed, whereas significant proportions of NK cells, monocytes and granulocytes persisted. CD45RA-depleted LPs contained effector and central memory CD4 þ and CD8 þ T cells that showed sustained IFN-g secretion to CMV, EBV, Aspergillus and Candida Ags. Alloreactivity was measured in MLRs between donors with complete HLA-mismatch. Alloreactive CD8 þ T cells were strongly reduced (median 41-log) upon CD45RA depletion, whereas alloreactive CD4 þ T cells persisted in significant numbers. In conclusion, clinical grade depletion of CD45RA þ naive T cells from donor LPs is feasible and highly efficient. The depleted products show sustained CD4 þ and CD8 þ T-cell reactivity to pathogens and effectively reduced CD8-mediated alloreactivity. Prophylactic and preemptive infusions after allogeneic SCT may improve T-cell reconstitution and pathogen-specific immunosurveillance, along with lower risk of inducing GVHD.

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Section: Discussionmentioning

confidence: 99%

Depletion of naive T cells using clinical grade magnetic CD45RA beads: a new approach for GVHD prophylaxis

Teschner

Distler

Wehler

et al. 2013

Bone Marrow Transplant

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“…After several rounds of stimulation and enrichment, the alloreactive population was cloned by limiting dilution at 0.5 cell/well [24]. CTL clones to cytomegalovirus (CMV) peptides VTEHDTLLY in HLA-A1 (clone 3c8) and NLVPMVATV in HLA-A2 (clone 18) were generated by single cell sorting of CD8 + T cells stained with the respective tetramers and expanded using phytohaemagglutinin stimulation [25]. HEK-293 and primary tubular epithelial cells (PTECs, line HK-2) were cultured in DMEM/F-12 medium (Invitrogen, Landsmeer, the Netherlands) supplemented with 2 mmol/l L-glutamine, 25 mmol/l HEPES, 50 U/ml penicillin and 50 μg/ml streptomycin (all purchased from Invitrogen) and, for PTECs, also 5 μg/ml insulin, 5 μg/ml transferrin, 5 ng/ml selenium, 36 ng/ml hydrocortisone and 10 ng/ml epidermal growth factor (all purchased from Sigma, Zwijndrecht, the Netherlands).…”

Section: Methodsmentioning

confidence: 99%

Immunogenicity of human embryonic stem cell-derived beta cells

et al. 2016

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Aims/hypothesis To overcome the donor shortage in the treatment of advanced type 1 diabetes by islet transplantation, human embryonic stem cells (hESCs) show great potential as an unlimited alternative source of beta cells. hESCs may have immune privileged properties and it is important to determine whether these properties are preserved in hESC-derived cells. Methods We comprehensively investigated interactions of both innate and adaptive auto-and allo-immunity with hESC-derived pancreatic progenitor cells and hESC-derived endocrine cells, retrieved after in-vivo differentiation in capsules in the subcutis of mice. Results We found that hESC-derived pancreatic endodermal cells expressed relatively low levels of HLA endorsing protection from specific immune responses. HLA was upregulated when exposed to IFNγ, making these endocrine progenitor cells vulnerable to cytotoxic T cells and alloreactive antibodies. In vivo-differentiated endocrine cells were protected from complement, but expressed more HLA and were targets for alloreactive antibody-dependent cellular cytotoxicity and alloreactive cytotoxic T cells. After HLA compatibility was provided by transduction with HLA-A2, preproinsulin-specific T cells killed insulin-producing cells. Conclusions/interpretation hESC-derived pancreatic progenitors are hypoimmunogenic, while in vivo-differentiated endocrine cells represent mature targets for adaptive immune responses. Our data support the need for immune intervention in transplantation of hESC-derived pancreatic progenitors. Cell-impermeable macro-encapsulation may suffice.

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“…32 Mismatches that are characterized by changes in amino acid residues not seen by the Tcell receptor, i.e. outside the α1/α2 domains for class I antigens, are not expected to be recognized and could, therefore, be considered as acceptable mismatches.…”

Section: Impact Of Single Mismatchesmentioning

confidence: 99%