Maintenance and targeting of bone marrow derived allo-reactive human plasma cells

Project: Research project

Description

Abstract Donor-specific alloantibodies (DSA) against HLA Class I and Class II are a majorproblem in organ transplantation. DSA can cause acute and chronic rejection and can be amajor barrier to finding an acceptable donor when present pre-transplant in ?sensitizedpatients?. Unfortunately, no effective therapy exists to either deplete DSAs or block their effect.Our prior studies suggested that bone marrow (BM)-derived long-lived plasma cells (LLPCs) area major source of persistent serum DSA. LLPCs are rare, poorly characterized and resistant tomost current therapy in vivo. The mechanism of resistance to therapy may be due to the factthat LLPCs reside in pro-survival microenvironments/niches in which supporting stromal cellsand leukocytes provide factors that enhance LLPCs longevity and prevent erstwhile apoptoticsignals. Due to difficulties in procuring, isolating, and culturing human BM LLPCs, much of thebiology of human PCs remains unclear and this has hindered the development of effectivetherapies. To overcome this problem, we developed an in vitro PC/stromal cell co-culture model.We now can maintain human PCs on mouse mesenchymal stromal cell (SC) lines in thepresence of recombinant human IL-6. After 6 weeks culture, these PCs retain the typical PCphenotype and robustly secrete IgG and IgA Igs. Using this novel system, we now are poised tostudy functional BM-derived PCs in vitro and interrogate factors responsible for their longevityand antibody production.
StatusFinished
Effective start/end date7/1/166/30/18

Funding

  • National Institutes of Health: $238,500.00

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Plasma Cells
Isoantibodies
Bone Marrow
Maintenance
Organ Transplantation
Stromal Cells
Coculture Techniques
Mesenchymal Stromal Cells
Immunoglobulin A
Antibody Formation
Interleukin-6
Leukocytes
Therapeutics
Cell Culture Techniques
Immunoglobulin G
Transplants
Cell Line
Survival
Serum
In Vitro Techniques