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Minor Antigen Vaccine-Sensitized DLI: In Vitro Responses Do Not Predict In Vivo Effects.

Steven Lawrence Rosinski¹, Brad Stone², Scott S Graves¹

¹Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA.; Department of Medicine, University of Washington, Seattle, WA.

Transplantation Direct

|July 19, 2016

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Minor histocompatibility antigen vaccination in dogs showed T cell responses against Y chromosome disparities. However, these responses were insufficient to drive anti-male immunity, suggesting other factors influence outcomes.

Area of Science:

Immunology
Transplantation Science

Background:

Pilot study investigating minor histocompatibility antigen (mHA) vaccination in a canine model.
Utilized constructs expressing male-specific gene disparities (mouse CDNA on Y and sex-determining region Y).
Reduced-intensity hematopoietic cell transplantation (HCT) performed with female donors and male recipients, establishing mixed chimeras.

Purpose of the Study:

To evaluate the efficacy of mHA vaccination in eliciting anti-male immune responses post-HCT.
To investigate the role of donor sensitization in response to Y-chromosome encoded antigens.
To assess the impact of booster vaccinations and donor lymphocyte infusion (DLI) on chimerism.

Main Methods:

Female donors and male recipients underwent HCT, creating mixed chimeras.

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Vaccine series administered to female donors, followed by DLI into recipients.

Booster vaccinations and a second DLI were administered to assess enhanced sensitization.

T cell responses assessed via ELISpot and intracellular cytokine staining.

RNA expression of target antigens evaluated in recipients.

Main Results:

One chimera showed a significant increase in donor chimerism after initial vaccination and DLI.
Booster vaccinations and a second DLI further increased chimerism in the same recipient.
Strong T cell responses observed in donors post-vaccination.
No significant change in donor chimerism observed in other recipients.
Antigen conversion occurred in the recipient expressing both target Y-chromosome genes.

Conclusions:

T cell responses to Y-chromosome encoded mHA disparities are not always sufficient for in vivo female anti-male responses.
Factors such as specific haplotypes and heterogeneous antigen expression may modulate T cell responses.
Future studies should explore larger cohorts and epigenetic modulation to enhance target gene expression.