Allogeneic bone marrow transplantation (BMT) can cure patients with risk acute myeloid leukemia (AML). Post-BMT recipients are highly susceptible to T cell responsive viral and fungal infections. We discovered that the BMT procedure itself was critical to the failure to cure AML. The fundamental realization was that the conditioning injured host secondary lymphoid organs. Key findings late post-BMT include: 1. Small lymph nodes (LNs) and disorganized microarchitecture;2. Low numbers of recent thymic emigrants and endogenously generated T cells, even at times late post-BMT, that localized to LNs where they receive the necessary signals to persist;3. Markedly diminished expression of T- and B-cell chemokines (CCL19, 21, CXCL13) and LN stromal cells depletion;4. Adenoviral CCL21 transduced dendritic cell vaccines or agonistic anti-lymphotoxin receptor (LT?R) mAb given to BMT recipients mediated restoration of CCL21 expression, improved LN architecture, increased LN size and T cell content, and augmented the endogenous immune response to pathogen, virus or AML challenge. These data led to our unifying and novel hypothesis that conditioning regimen-induced LN stromal injury is a major impediment to T cell and B cell immune system recovery post-BMT, predisposing the recipient to succumb to infections with pathogens and tumor recurrence. LN organogenesis is dependent upon lymphotoxin-?1?2, expressed on activated T-cells, B-cells and lymphoid tissue inducer cells, binding to LN stromal cells. Since there is a profound reduction in na?ve T- and B-cells and lymphoid tissue inducer cells in the LN late post-BMT, insufficient lymphotoxin signals are available, stromal derived T- and B-cell chemoattractants are not produced, and the LN is inadequate to support T cell priming and survival. We hypothesize that T cell mislocalization may substantially contribute to post-BMT immune deficiency.
Our aims are to test the hypothesis that: 1. Chemokines and lymphotoxin-? signals to regenerate LN stroma will facilitate T-cell recruitment into and within the LN. Hypothesis: LN stroma regeneration will increase immune function. Chemokine upregulation and lymphotoxin-? signals will be evaluated for LN repair and graft-versus-host disease (GVHD) risk under conditions that cause different degrees of LN stromal injury due to effects of age, conditioning and allogenicity. LN regeneration strategies will include: dendritic cell delivery of CCL21 or CXCL13 chemokines, LT?/? signals via agonistic anti-LT?R mAb or lymphoid tissue inducer cell infusion;and 2. Regenerating the LN stroma will augment T cell responses to AML, pathogen(s) and viruses without increasing GVHD. Hypothesis: Augmented recovery of endogenous immune function by regenerating LN stroma post-BMT leads to greater clearance of AML, pathogens and viruses. Challenge of post-BMT recipients with Listeria monocytogenes, vesicular stomatitis virus or murine cytomegalovirus will be used to assess na?ve and effector/memory responses to pathogens in BMT recipients after LN regeneration.

Public Health Relevance

Our studies to understand the nature of this defect and regenerate the lymph node (LN) microenvironment will help save lives by optimizing the therapeutic potential of donor lymphocytes and adoptive T cell transfer in the increasingly aged bone marrow transplant recipient and in patients with known LN injury (e.g. HIV/AIDS patients with LN fibrosis) whose immune system may benefit from LN regeneration approaches.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA072669-17
Application #
8588898
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Mccarthy, Susan A
Project Start
1997-04-01
Project End
2017-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
17
Fiscal Year
2014
Total Cost
$264,668
Indirect Cost
$90,544
Name
University of Minnesota Twin Cities
Department
Pediatrics
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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