Baylor Institute for Immunology Research

Rocha, V., A. Ruggeri, S. Spellman, T. Wang, R. Sobecks, F. Locatelli, M. Askar, G. Michel, W. Arcese, A. P. Iori, D. Purtill, R. Danby, G. F. Sanz, E. Gluckman and M. Eapen (2016). “Killer cell immunoglobulin-like receptor-ligand matching and outcomes after unrelated cord blood transplantation in acute myeloid leukemia.” Biol Blood Marrow Transplant 22(7): 1284-1289.

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The effect of killer cell immunoglobulin-like receptor (KIR)-ligand matching on outcomes after unrelated cord blood (CB) transplantation was studied in 461 patients with acute myeloid leukemia, categorizing KIR ligand for HLA-C groups C1 and C2 and Bw4. Donor-recipient HLA matching considered allele-level matching at HLA-A, -B, -C, and -DRB1. Separate analyses were conducted for 6-7/8 HLA-matched and 3-5/8 HLA-matched transplants because HLA matching confounded KIR-ligand matching (ie, KIR-ligand mismatching was less likely with better HLA matching). All patients received single CB unit and myeloablative conditioning. There were no significant differences in nonrelapse mortality (NRM), relapse, and overall mortality by KIR-ligand match status. However, among recipients of 3-5/8 HLA-matched transplants, NRM (HR, 2.26; P = .008) and overall mortality (HR, 1.78; P = .008) but not relapse were higher with KIR-ligand mismatched (host-versus-graft direction) compared with KIR-ligand matched transplants. These data do not support selecting CB units based on KIR-ligand match status for transplants mismatched at 1 or 2 HLA loci. Although transplants mismatched at 3 or more HLA loci are not recommended, avoiding KIR-ligand mismatching in this setting lowers mortality risks.

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Improved antigenicity against HIV-1 envelope (Env) protein is needed to elicit vaccine-induced protective immunity in humans. Here we describe the first tests in non-human primates (NHPs) of Env gp140 protein fused to a humanized anti-LOX-1 recombinant antibody for delivering Env directly to LOX-1-bearing antigen presenting cells, especially dendritic cells (DC). LOX-1, or 1ectin-like oxidized low-density lipoprotein (LDL) receptor-1, is expressed on various antigen presenting cells and endothelial cells, and is involved in promoting humoral immune responses. The anti-LOX-1 Env gp140 fusion protein was tested for priming immune responses and boosting responses in animals primed with replication competent NYVAC-KC Env gp140 vaccinia virus. Anti-LOX-1 Env gp140 vaccination elicited robust cellular and humoral responses when used for either priming or boosting immunity. Co-administration with Poly ICLC, a TLR3 agonist, was superior to GLA, a TLR4 agonist. Both CD4+ and CD8+ Env-specific T cell responses were elicited by anti-LOX-1 Env gp140, but in particular the CD4+ T cells were multifunctional and directed to multiple epitopes. Serum IgG and IgA antibody responses induced by anti-LOX-1 Env gp140 against various gp140 domains were cross-reactive across HIV-1 clades; however, the sera neutralized only HIV-1 bearing sequences most similar to the clade C 96ZM651 Env gp140 carried by the anti-LOX-1 vehicle. These data, as well as the safety of this protein vaccine, justify further exploration of this DC-targeting vaccine approach for protective immunity against HIV-1.

Lazaryan, A., T. Wang, S. R. Spellman, H. L. Wang, J. Pidala, T. Nishihori, M. Askar, R. Olsson, M. Oudshoorn, H. Abdel-Azim, A. Yong, M. Gandhi, C. Dandoy, B. Savani, G. Hale, K. Page, M. Bitan, R. Reshef, W. Drobyski, S. G. Marsh, K. Schultz, C. R. Muller, M. A. Fernandez-Vina, M. R. Verneris, M. M. Horowitz, M. Arora, D. J. Weisdorf and S. J. Lee (2016). “Human leukocyte antigen supertype matching after myeloablative hematopoietic cell transplantation with 7/8 matched unrelated donor allografts: A report from the center for international blood and marrow transplant research.” Haematologica: May 2016 [Epub ahead of print].

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The diversity of the human leukocyte antigen (HLA) class I and II alleles can be simplified by consolidating them into fewer supertypes based on functional or predicted structural similarities in epitope binding grooves of HLA molecules. We studied the impact of matched and mismatched HLA-A (265 vs. 429), -B (230 vs. 92), -C (365 vs. 349), and -DRB1 (153 vs. 51) supertypes on clinical outcomes of 1934 patients with acute leukemias or myelodysplasia/myeloproliferative disorders. All patients were reported to the Center for International Blood and Marrow Transplant Research following single-allele mismatched unrelated donor myeloablative conditioning hematopoietic cell transplantation. Single mismatched alleles were categorized into 6 HLA-A (A01, A01A03, A01A24, A02, A03, A24), 6 HLA-B (B07, B08, B27, B44, B58, B62), 2 HLA-C (C1, C2), and 5 HLA-DRB1 (DR1, DR3, DR4, DR5, DR9) supertypes. Supertype B mismatch was associated with increased risk of grade II-IV acute graft-versus-host disease (hazard ratio =1.78, p=0.0025) compared to supertype B match. Supertype B07-B44 mismatch was associated with a higher incidence of both grade II-IV (hazard ratio=3.11, p=0.002) and III-IV (hazard ratio=3.15, p=0.01) acute graft-versus-host- disease. No significant associations were detected between supertype-matched versus -mismatched groups at other HLA loci. These data suggest that avoiding HLA-B supertype mismatches can mitigate the risk of grade II-IV acute graft-versus-host disease in 7/8-mismatched unrelated donor hematopoietic cell transplantation when multiple HLA-B supertype-matched donors are available, and call for future studies to define the mechanisms by which supertype mismatching affects outcomes after alternative donor hematopoietic cell transplantation.

Salabert, N., B. Todorova, F. Martinon, R. Boisgard, G. Zurawski, S. Zurawski, N. Dereuddre-Bosquet, A. Cosma, T. Kortulewski, J. Banchereau, Y. Levy, R. Le Grand and C. Chapon (2016). “Intradermal injection of an anti-langerin-hivgag fusion vaccine targets epidermal langerhans cells in nonhuman primates and can be tracked in vivo.” European Journal of Immunology 46(3): 689-700.

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The development of new immunization strategies requires a better understanding of early molecular and cellular events occurring at the site of injection. The skin is particularly rich in immune cells and represents an attractive site for vaccine administration. Here, we specifically targeted vaccine antigens to epidermal Langerhans cells (LCs) using a fusion protein composed of HIV antigens and a monoclonal antibody targeting Langerin. We developed a fluorescence imaging approach to visualize, in vivo, the vaccine-targeted cells. Studies were performed in nonhuman primates (NHPs) because of their relevance as a model to assess human vaccines. We directly demonstrated that in NHPs, intradermally injected anti-Langerin-HIVGag specifically targets epidermal LCs and induces rapid changes in the LC network, including LC activation and migration out of the epidermis. Vaccine targeting of LCs significantly improved anti-HIV immune response without requirement of an adjuvant. Although the co-injection of the TLR-7/8 synthetic ligand, R-848 (resiquimod), with the vaccine, did not enhance significantly the antibody response, it stimulated recruitment of HLA-DR+ inflammatory cells to the site of immunization. This study allowed us to characterize the dynamics of early local events following the injection of a vaccine-targeted epidermal LCs and R-848.

Blanco, P., H. Ueno and N. Schmitt (2016). “T follicular helper (Tfh) cells in lupus: Activation and involvement in SLE pathogenesis.” Eur J Immunol 46(2): 281-290.

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Systemic lupus erythematosus (SLE) is a chronic systemic inflammatory autoimmune disease characterized by a breakdown of tolerance to self. The autoantibodies generated in SLE are directed against nuclear components, with which they form immune complexes (ICs). ICs play key roles in organ and tissue damage, as well as in the activation of the innate and adaptive immune system during the disease course. Therefore, it is of prime importance to understand the mechanisms responsible for the development of B cells producing these pathogenic autoantibodies. There is compelling evidence that T follicular helper (Tfh) cells play a fundamental role in this process. In this review, we will summarize the current knowledge regarding the involvement of Tfh cells in SLE pathogenesis, and discuss potential strategies to target Tfh cells and/or molecules as a therapeutic modality of SLE.