Baylor Institute for Immunology Research

Askar, M. (2017). “The killer immunoglobulin-like receptor dilemma: How do we harness the power of killer immunoglobulin-like receptors?” Biol Blood Marrow Transplant 23(4): 535-536.

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Alloreactive natural killer (NK) cells have been reported to significantly impact allogeneic hematopoietic cell transplantation (HCT) outcomes. How the interactions between killer immunoglobulin-like receptors (KIR) and HLA influence human NK cell functions has been demonstrated by elegant in vitro experiments [1]. Since the early 2000s, the published literature has been populated with numerous studies investigating the association between KIR genotype/haplotype and clinical outcomes of HCT, both independently and in the context of interaction with corresponding HLA ligands. Meanwhile, additional models for KIR modulation of NK cell functions have been proposed [2]. The method of KIR typing adds another layer of complexity in studying the associations between KIR and HCT outcomes. Most published studies in this domain rely on logistically attractive genotyping methods that allow identification of all KIR genes from archived DNA samples collected routinely for HLA typing and typically tested in large batches. In contrast, flow cytometry–based phenotyping and RNA-based transcription profile testing require freshly collected samples and are more technically involved. Leung et al. have demonstrated significant heterogeneity in the level of KIR expression by NK cells with more than 10-fold difference observed among individuals with similar genotype; they have also demonstrated that transcripts of only 2 of 12 KIR genes tested (KIR2DL3 and KIR3DL2) were consistently detectable by real time PCR [3]. These results suggest the potential relevance of phenotyping, rather than genotyping, in KIR-based selection of HCT donors. Lastly, different alleles of a KIR gene were reported to have different functional properties, such as licensing capability, durability of surface expression after ligand interaction, and intracellular signaling [4].

Askar, M., R. Sobecks, T. Wang, M. Haagenson, N. Majhail, A. Madbouly, D. Thomas, A. Zhang, K. Fleischhauer, K. Hsu, M. Verneris, S. J. Lee, S. R. Spellman and M. Fernandez-Vina (2017). “Mhc class i chain-related gene a (mica) donor-recipient mismatches and mica-129 polymorphism in unrelated donor hematopoietic cell transplantations has no impact on outcomes in acute lymphoblastic leukemia, acute myeloid leukemia, or myelodysplastic syndrome: A center for international blood and marrow transplant research study.” Biol Blood Marrow Transplant 23(3): 436-444.

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Single-center studies have previously reported associations of MHC Class I Chain-Related Gene A (MICA) polymorphisms and donor-recipient MICA mismatching with graft-versus-host disease (GVHD) after unrelated donor hematopoietic cell transplantation (HCT). In this study, we investigated the association of MICA polymorphism (MICA-129, MM versus MV versus VV) and MICA mismatches after HCT with 10/10 HLA-matched (n = 552) or 9/10 (n = 161) unrelated donors. Included were adult patients with a first unrelated bone marrow or peripheral blood HCT for acute lymphoblastic leukemia, acute myeloid leukemia, or myelodysplastic syndrome that were reported to the Center for International Blood and Marrow Transplant Research between 1999 and 2011. Our results showed that neither MICA mismatch nor MICA-129 polymorphism were associated with any transplantation outcome (P < .01), with the exception of a higher relapse in recipients of MICA-mismatched HLA 10/10 donors (hazard ratio [HR], 1.7; P = .003). There was a suggestion of association between MICA mismatches and a higher risk of acute GVHD grades II to IV (HR, 1.4; P = .013) There were no significant interactions between MICA mismatches and HLA matching (9/10 versus 10/10). In conclusion, the findings in this cohort did not confirm prior studies reporting that MICA polymorphism and MICA mismatches were associated with HCT outcomes.

Zurawski, G., X. Shen, S. Zurawski, G. D. Tomaras, D. C. Montefiori, M. Roederer, G. Ferrari, C. Lacabaratz, P. Klucar, Z. Wang, K. E. Foulds, S. F. Kao, X. Yu, A. Sato, N. L. Yates, C. LaBranche, S. Stanfield-Oakley, K. Kibler, B. Jacobs, A. Salazar, S. Self, J. Fulp, R. Gottardo, L. Galmin, D. Weiss, A. Cristillo, G. Pantaleo and Y. Levy (2017). “Superiority in rhesus macaques of targeting hiv-1 env gp140 to cd40 versus lox-1 in combination with replication competent nyvac-kc for induction of env-specific antibody and t cell responses.” J Virol: 2017 Feb [Epub ahead of print].

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We compared the HIV-1-specific immune responses generated by targeting HIV-1 envelope protein (Env gp140) to either CD40 or LOX-1, two endocytic receptors on dendritic cells (DCs), in Rhesus macaques primed with a poxvirus vector (NYVAC-KC) expressing Env gp140. The DC-targeting vaccines, humanized recombinant monoclonal antibodies fused to Env gp140, were administered as a boost with poly ICLC adjuvant either alone or co-administered with the NYVAC-KC vector. All the DC-targeting vaccine administrations with poly ICLC increased the low-level serum anti-Env IgG responses elicited by NYVAC-KC priming significantly more (up to P =0.01) than a group without poly ICLC. The responses were robust, cross-reactive, and contained antibodies specific to multiple epitopes within gp140 including the C1, C2, V1-3, C4, C5, and gp41 immuno-dominant regions. The DC-targeting vaccines also elicited modest serum Env-specific IgA responses. All groups gave serum neutralization activity limited to Tier 1 viruses and antibody dependent cytotoxicity responses (ADCC) after DC-targeting boosts. Furthermore, CD4+ and CD8+ T cell responses specific to multiple Env epitopes were strongly boosted by the DC-targeting vaccines + poly ICLC. Together, these results indicate that prime/boost immunization via NYVAC-KC and either alphaCD40.Env gp140/poly ICLC or alphaLOX-1.Env gp140/poly ICLC induced balanced antibody and T cell responses against HIV-1 Env. Co-administration of NYVAC-KC with the DC-targeting vaccines increased T cell responses, but had minimal effects on antibody responses except for suppressing serum IgA responses. Overall, compared to LOX-1, targeting Env to CD40 gave more robust T cell and serum antibody responses with broader epitope representation and greater durability.IMPORTANCE An effective vaccine to prevent HIV-1 infection does not yet exist. An approach to elicit strong protective antibody development is to direct virus protein antigens specifically to dendritic cells, which are now known to be the key cell type for controlling immunity. Here we have tested in non-human primates two prototype vaccines engineered to direct the HIV-1 coat protein Env to dendritic cells. These vaccines bind to either CD40 or LOX-1, two dendritic cell surface receptors with different functions and tissue distributions. We tested the vaccines described above in combination with attenuated virus vectors that express Env. Both vaccines, but especially that delivered via CD40, raised robust immunity against HIV-1 as measured by monitoring potentially protective antibody and T cell responses in the blood. The safety and efficacy of the CD40-targeted vaccine justifies further development for future human clinical trials.

Chen, Y. B., T. Wang, M. T. Hemmer, C. Brady, D. R. Couriel, A. Alousi, J. Pidala, A. Urbano-Ispizua, S. W. Choi, T. Nishihori, T. Teshima, Y. Inamoto, B. Wirk, D. I. Marks, H. Abdel-Azim, L. Lehmann, L. Yu, M. Bitan, M. S. Cairo, M. Qayed, R. Salit, R. P. Gale, R. Martino, S. Jaglowski, A. Bajel, B. Savani, H. Frangoul, I. D. Lewis, J. Storek, M. Askar, M. A. Kharfan-Dabaja, M. Aljurf, O. Ringden, R. Reshef, R. F. Olsson, S. Hashmi, S. Seo, T. R. Spitzer, M. L. MacMillan, A. Lazaryan, S. R. Spellman, M. Arora and C. S. Cutler (2017). “Gvhd after umbilical cord blood transplantation for acute leukemia: An analysis of risk factors and effect on outcomes.” Bone Marrow Transplant 52(3): 400-408.

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Using the Center for International Blood and Marrow Transplant Research (CIBMTR) registry, we analyzed 1404 umbilical cord blood transplantation (UCBT) patients (single (<18 years)=810, double (18 years)=594) with acute leukemia to define the incidence of acute GvHD (aGvHD) and chronic GvHD (cGvHD), analyze clinical risk factors and investigate outcomes. After single UCBT, 100-day incidence of grade II-IV aGvHD was 39% (95% confidence interval (CI), 36-43%), grade III-IV aGvHD was 18% (95% CI, 15-20%) and 1-year cGvHD was 27% (95% CI, 24-30%). After double UCBT, 100-day incidence of grade II-IV aGvHD was 45% (95% CI, 41-49%), grade III-IV aGvHD was 22% (95% CI, 19-26%) and 1-year cGvHD was 26% (95% CI, 22-29%). For single UCBT, multivariate analysis showed that absence of antithymocyte globulin (ATG) was associated with aGvHD, whereas prior aGvHD was associated with cGvHD. For double UCBT, absence of ATG and myeloablative conditioning were associated with aGvHD, whereas prior aGvHD predicted for cGvHD. Grade III-IV aGvHD led to worse survival, whereas cGvHD had no significant effect on disease-free or overall survival. GvHD is prevalent after UCBT with severe aGvHD leading to higher mortality. Future research in UCBT should prioritize prevention of GvHD.

Askar, M. (2017). “The killer immunoglobulin-like receptor dilemma: How do we harness the power of killer immunoglobulin-like receptors?” Biol Blood Marrow Transplant: 2017 Feb [Epub ahead of print].

Full text of this article.

Alloreactive natural killer (NK) cells have been reported to significantly impact allogeneic hematopoietic cell transplantation (HCT) outcomes. How the interactions between killer immunoglobulin-like receptors (KIR) and HLA influence human NK cell functions has been demonstrated by elegant in vitro experiments [1]. Since the early 2000s, the published literature has been populated with numerous studies investigating the association between KIR genotype/haplotype and clinical outcomes of HCT, both independently and in the context of interaction with corresponding HLA ligands. Meanwhile, additional models for KIR modulation of NK cell functions have been proposed [2]. The method of KIR typing adds another layer of complexity in studying the associations between KIR and HCT outcomes. Most published studies in this domain rely on logistically attractive genotyping methods that allow identification of all KIR genes from archived DNA samples collected routinely for HLA typing and typically tested in large batches.