Biomarker for transplantation tolerance induced by apoptotic donor leukocytes
AssigneeRegents of the University of Minnesota
InventorsAmar Singh, Bernhard J. Hering, Sabarinathan Ramachandran
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Abstract
In certain embodiments, the present invention provides methods of identifying and treating a transplant recipient patient having transplantation tolerance induced by apoptotic donor leukocytes infused under cover of transient immunotherapy.
Claims19
A method of identifying a transplant recipient patient having transplantation tolerance induced by donor antigen administered under cover of transient immunotherapy, comprising:
- (a) assaying a first blood sample from the patient to detect a baseline frequency of target cells, wherein the first blood sample is obtained pre-tolerization, pre-transplant, and pre-initiation of transient immunotherapy,
- (b) assaying a second blood sample from the patient to detect a post-procedure frequency of target cells, wherein the second sample is obtained post-tolerization, post-transplant, and post-initiation of transient immunotherapy;
- and
- (c) identifying the patient as having transplantation tolerance/immune acceptance induced by the donor antigen when the post-procedure frequency is at least 1.5-fold greater than the baseline frequency,
- wherein the target cells are T regulatory (Treg) cells having one or more combination of markers HelioshiUSP22hi, CCR2hiTIGIThi, CCR2hiTIGIThiAreg+, and/or CD4+CD25+CD127−FOXP3+;
- and/or
- wherein the target cells are T regulatory Type 1 (Tr1) cells having one or more combination of markers PD-1hiCD69hiHelioshi, TIGIThi CCR2hiST2hi GrzB+FOXP3−, Areghi TIGIThi CCR2hi GrnzB+ ST2hi FOXP3− and/or CD4+CD49b+LAG3+;
- and/or
- wherein the target cells are exhaust CD4 T cells (Tex) having markers PD-1+EOMES+ CD127hi Helios+TOX+TCF-1−.
A method, comprising:
- (a) obtaining a first blood sample from a transplant recipient patient to detect a baseline frequency of target cells, wherein the first blood sample is obtained pre-tolerization, pre-transplant, and pre-initiation of transient immunotherapy,
- (b) obtaining a second blood sample from the patient to detect a post-procedure frequency of target cells, wherein the second sample is obtained post-tolerization, post-transplant, and post-initiation of transient immunotherapy,
- (c) assaying the first and second blood samples to detect levels of target cells before and after tolerization, and
- (d) identifying the transplant recipient patient as having transplantation tolerance/immune acceptance induced by donor antigens infused under cover of transient immunotherapy when the post-procedure frequency is at least 1.5-fold greater than the baseline frequency,
- wherein the target cells are T regulatory (Treg) cells having one or more combination of markers HelioshiUSP22hi, CCR2hiTIGIThi, CCR2hiTIGIThiAreg+, and/or CD4+CD25+CD127−FOXP3+;
- and/or
- wherein the target cells are T regulatory Type 1 (Tr1) cells having one or more combination of markers PD-1hiCD69hiHelioshi, TIGIThi CCR2hiST2hiGrnzB+FOXP3−, Areghi TIGIThi CCR2hi GrnzB+ST2hi FOXP3− and/or CD4+CD49b+LAG3+;
- and/or
- wherein the target cells are exhaust CD4 T cells (Tex) having one or more combination of markers PD-1+EOMES+ CD127hi Helios+TOX+TCF-1−,
- wherein the identification is with a multiparameter single flowcytometry panel comprising 12 binding reagents that specifically recognize CD4, FOXP3, CD49b, LAG-3, PD-1, Helios/USP22, CCR2, ST2, TIGIT, TOX/EOMES, CD127, and Areg to determine these regulatory and exhaust subsets.
A kit comprising a panel of binding reagents, wherein the reagents individually specific for CD4, CD127, FOXP3 (i.c.), Areg, CD49b, LAG-3, ST2, CCR2, PD-1, TOX/EOMES (i.c.), TIGIT, and Helios and/or USP22.
Dependencies are inferred from the claim text.