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Mechanisms controlling transfusion-associated antibody responses in SCD alloimmunization

Award Number: R01HL130139
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2016
PERIOD OF PERFORMANCE END DATE: 01/31/2022

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Mechanisms controlling transfusion-associated antibody responses in SCD alloimmunization - DESCRIPTION (provided by applicant): Transfusion therapy remains an important treatment modality for patients with sickle cell disease (SCD). However, some patients develop antibodies against the allogeneic transfused cells, causing major life- threatening complications for the patient. Understanding the immune triggers of alloimmunization and why some patients develop these antibodies is likely to lead to development of diagnostic as well as therapeutic interventions. T follicular helper (TFH) cells provide help to B cells in the generation of antibod responses as well as in production of long-lasting IgG antibodies and are likely to be involved in alloimmunization biology. Exiting new studies have found TFH related cells in the circulation in humans and mice expressing similar markers as lymphoid TFH cells (including CXCR5, ICOS, CD40L, IL-21) that can promote antibody production and their levels correlate with autoantibodies and levels of protective antibodies. Different circulating TFH subsets displaying TH1, TH2 and TH17 like effector functions have been identified. Intriguingly, TIGIT and PD-1 are also expressed on TFH cells, although their relationship to specific effector functions has not been described. These molecules are considered "exhaustion markers" or "immune checkpoints" expressed following chronic antigen stimulation and associated with low type I responses. Alloimmunization occurring after repeated transfusions could embody a similar model of repeated/chronic stimulation and be impacted by the expression of these 2 molecules on TFH cells. Our preliminary data indicate that TIGIT can indeed identify a subset of blood TFH cells with potent TFH functions and low TH1 like response as compared to TFH cells lacking TIGIT. These data suggest that upregulation of TIGIT (and PD-1) pathways on TFH cells may be directly involved in phenotype plasticity from differentiated CD4+ TFH cells displaying type 1 like properties toward strong B cell help. We further hypothesize that TIGIT (and PD-1) triggering on TFH cells is heightened in alloimmunized as compared to non-alloimmunized patients. To test these hypotheses, we will first examine the molecular regulation by TIGIT pathway on circulating TFH cells in driving robust TFH versus type-1 responses. We will then determine whether PD-1 on TIGIT-expressing TFH cells has overlapping or additive role to TIGIT in TFH function and polarization. Finally, we will determine whether TIGIT-dependent T FH functions differ in chronically transfused alloimmunized as compared to non-alloimmunized patients with SCD patients. Together, these data will determine whether alterations in TIGIT (and PD-1) pathway contributes to the plasticity of TFH effector functions and provide a better understanding of the TFH-related correlates of alloantibody response in SCD patients . Understanding the molecular mechanisms of how TFH cells drive alloimmunization in SCD m ay help toward future identification of biomarkers of alloimmunization and therapeutic strategies for its prevention in this vulnerable population.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2023 ( Subtotal = -$35 )
2023	2020	NEW YORK BLOOD CENTER, INC.	310 E 67TH ST	NEW YORK	NY	10065	NEW YORK	USA	Blood Diseases and Resources Research	000	5	5/15/2023	NON-COMPETING CONTINUATION	-$35
														Subtotal = -$35

Issue Date FY: 2022 ( Subtotal = -$19 )
2022	2020	NEW YORK BLOOD CENTER, INC.	310 E 67TH ST	NEW YORK	NY	10065	NEW YORK	USA	Blood Diseases and Resources Research	000	5	7/13/2022	NON-COMPETING CONTINUATION	-$19
														Subtotal = -$19

Issue Date FY: 2020 ( Subtotal = $426,500 )
2020	2020	NEW YORK BLOOD CENTER, INC., THE	310 E 67TH ST	NEW YORK	NY	10065	NEW YORK	USA	Blood Diseases and Resources Research	000	5	1/28/2020	NON-COMPETING CONTINUATION	$426,500
														Subtotal = $426,500

Issue Date FY: 2019 ( Subtotal = $426,500 )
2019	2019	NEW YORK BLOOD CENTER, INC., THE	310 E 67TH ST	NEW YORK	NY	10065	NEW YORK	USA	Blood Diseases and Resources Research	000	4	2/1/2019	NON-COMPETING CONTINUATION	$426,500
														Subtotal = $426,500

Issue Date FY: 2018 ( Subtotal = $426,500 )
2018	2018	NEW YORK BLOOD CENTER, INC., THE	310 E 67TH ST	NEW YORK	NY	10065	NEW YORK	USA	Blood Diseases and Resources Research	000	3	2/1/2018	NON-COMPETING CONTINUATION	$417,970
2018	2018	NEW YORK BLOOD CENTER, INC., THE	310 E 67TH ST	NEW YORK	NY	10065	NEW YORK	USA	Blood Diseases and Resources Research	001	3	5/12/2018	NON-COMPETING CONTINUATION	$8,530
														Subtotal = $426,500

Issue Date FY: 2017 ( Subtotal = $426,500 )
2017	2017	NEW YORK BLOOD CENTER, INC., THE	310 E 67TH ST	NEW YORK	NY	10065	NEW YORK	USA	Blood Diseases and Resources Research	000	2	1/16/2017	NON-COMPETING CONTINUATION	$426,500
														Subtotal = $426,500

Issue Date FY: 2016 ( Subtotal = $426,500 )
2016	2016	New York Blood Center, Inc.	310 EAST 67TH STREET	NEW YORK	NY	10065	NEW YORK	USA	Cardiovascular Diseases Research	000	1	4/26/2016	NEW	$426,500
														Subtotal = $426,500

Grand Total All Awards = $2,132,446

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Mechanisms controlling transfusion-associated antibody responses in SCD alloimmunization

Award Number: R01HL130139

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 05/01/2016

PERIOD OF PERFORMANCE END DATE: 01/31/2022

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