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Systemic dendritic cell mobilization associated with administration of FLT3 ligand to SIV- and SHIV-infected macaques
R Keith Reeves1, Qing Wei, Jackie Stallworth
1Department of Microbiology, University of Alabama at Birmingham (UAB), Birmingham, Alabama 35294, USA.
Abstract:
Reports indicate that myeloid and plasmacytoid dendritic cells (mDCs and pDCs), which are key effector cells in host innate immune responses, can be infected with HIV-1 and are reduced in number and function during the chronic phase of HIV disease. Furthermore, it was recently demonstrated that a sustained loss of mDCs and pDCs occurs in SIV-infected macaques. Since loss of functional DC populations might impair innate immune responses to opportunistic microorganisms and neoplastic cells, we explored whether inoculation of naive and SIV- or SHIV-infected pigtailed macaques with the hematopoietic cytokine FLT3-ligand (FLT3-L) would expand the number of mDCs and pDCs in vivo. After the macaques received supraphysiologic doses of FLT3-L, mDCs, pDCs, and monocytes increased up to 45-fold in blood, lymph nodes, and bone marrow (BM), with DC expansion in the BM preceding mobilization in blood and lymphoid tissues. FLT3-L also increased serum levels of IL-12, at least transiently, and elicited higher surface expression of HLA-DR and the activation markers CD25 and CD69 on NK and T cells. During and after treatment of infected animals, APCs increased in number and were activated; however, CD4(+) T cell numbers, virion RNA, and anti-SIV/SHIV antibody titers remained relatively stable, suggesting that FLT3-L might be a safe modality to expand DC populations and provide therapeutic benefit during chronic lentivirus infections.
Insights
Hematopoietic cytokine FLT3-ligand (FLT3-L) safely expands myeloid and plasmacytoid dendritic cells (mDCs and pDCs) in macaques with lentivirus infections. This expansion may offer therapeutic benefits for innate immune response restoration.
Area of Science:
- Immunology
- Virology
- Hematology
Background:
- Myeloid and plasmacytoid dendritic cells (mDCs and pDCs) are crucial for innate immunity but are depleted during chronic HIV and SIV infections.
- Loss of functional dendritic cells (DCs) can compromise immune responses against opportunistic pathogens and cancer.
- Previous studies show mDC and pDC loss in SIV-infected macaques.
Purpose of the Study:
- To investigate if FLT3-ligand (FLT3-L) can expand mDCs and pDCs in naive and SIV/SHIV-infected pigtailed macaques.
- To assess the safety and potential therapeutic benefit of FLT3-L in lentivirus infection models.
Main Methods:
- Administration of supraphysiologic doses of FLT3-L to naive and SIV/SHIV-infected pigtailed macaques.
- Monitoring of mDC, pDC, and monocyte populations in blood, lymph nodes, and bone marrow.
- Analysis of serum IL-12 levels, HLA-DR, CD25, CD69 expression on immune cells, CD4(+) T cell counts, viral RNA, and antibody titers.
Main Results:
- FLT3-L treatment led to a significant expansion (up to 45-fold) of mDCs, pDCs, and monocytes in various tissues.
- DC expansion in bone marrow preceded mobilization to blood and lymphoid tissues.
- FLT3-L transiently increased IL-12, enhanced HLA-DR and activation marker expression on NK and T cells, and increased APC numbers and activation in infected animals, without altering CD4(+) T cell counts or viral load.
Conclusions:
- FLT3-L is a safe modality for expanding dendritic cell populations in vivo.
- FLT3-L administration shows potential therapeutic benefits in chronic lentivirus infections by restoring innate immune cell numbers and function.
- Further research is warranted to explore FLT3-L's efficacy in managing lentiviral infections.
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