The vastly diverse antigen receptor genes are assembled from numerous V, D and J coding segments via the lymphoid specific DNA rearrangement, V(D)J recombination. Defective V(D)J recombination impairs lymphocyte development and thus, results in immunodeficiency. The non-homologous end joining (NHEJ) pathway is required during V(D)J recombination by virtue of its role as one of the major DNA double strand break (DSB) repair pathways. Mutations in nearly all of the NHEJ genes have been found in association with human primary immunodeficiency syndromes. ARTEMIS is the most frequently mutated NHEJ gene and was initially discovered in the radiation sensitive severe combined immunodeficiency syndrome, RS-SCID. NHEJ- deficient patients can undergo hematopoietic cell transplantation to reconstitute T and B cell functions. However, because NHEJ is critical for DSB repair in all cell types, conditioning regimens involving radiation cause excessive tissue damage and can lead to mortality. ARTEMIS-deficient patients have been successfully engrafted with T and B cells with myeloablative conditioning using alkylating agents. However, these patients exhibit late complications including growth failure, endocrine deficiencies and dental abnormalities. The goals of this proposal are to elucidate the mechanisms underlying the toxicities associated with myeloablative conditioning with alkylating agents using our previously developed and characterized mouse models of NHEJ- deficient SCID and to determine the efficacy of alternative conditioning regimens. The potential for late onset tumorigenesis associated will also be examined. Together, these studies will provide mechanistic insight into the causes of late toxicities in NHEJ-deficient primary immunodeficiencies and potentially lead to the development of more effective therapies.

Public Health Relevance

The goals of the proposed research are to identify the underlying causes of late complications arising in Artemis-deficient SCID patients who have undergone myeloablative conditions regimens prior to bone marrow transplantation. Patients who were conditioned with alkylator agents exhibited growth retardation, late-onset endocrinologic deficiencies, and dental abnormalities. The causes of these complications will be analyzed using a mouse model of Artemis-deficient SCID developed in our lab. Moreover, we will examine the impact of alternative conditioning regimens on the observed late toxicities. The ultimate goals of these studies are to prevent or treat late complications caused by current conditioning regimens and to identify improved, less toxic treatments for bone marrow transplantation of Artemis-deficient and other radiation sensitive SCID patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI122244-01A1
Application #
9251366
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Voulgaropoulou, Frosso
Project Start
2017-07-20
Project End
2019-06-30
Budget Start
2017-07-20
Budget End
2018-06-30
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109