Simultaneous blockade of the CD40 and CD28 costimulatory pathways is an effective treatment strategy to promote allograft acceptance but does not lead to indefinite allograft survival. The immune mechanisms responsible for costimulation-independent rejection are not defined. Here we have studied the rejection responses of murine C57BL/6 recipients, which we show to be relatively resistant to inhibition by combined CD40/CD28 blockade. We demonstrate that asialo GM1 + CD8 + cells play a critical role in this costimulation blockade-resistant rejection. These results provide new insights into the costimulatory requirements for T-cell subsets and demonstrate for the first time that combined blockade of the CD40 and CD28 pathways does not adequately inhibit CD8-mediated skin allograft rejection. Furthermore, we provide evidence that asialo GM1 is a potentially important therapeutic target for CD8-dependent immune responses.

Blockade of the CD40 pathway with anti-CD40 mAb is immunosuppressive in a large animal, preclinical renal transplant model. The potential effect of this therapy on viral immune responses will be important to consider for the design of safe clinical trials.

Simultaneous blockade of the CD40 and CD28 T cell costimulatory pathways effectively promotes skin allograft survival in C3H/HeJ mice, extending median survival times (MSTs) beyond 100 days. This strategy is markedly less effective in C57BL/6 mice, with MSTs ranging between 20 and 30 days. In this study, we investigate the underlying genetic causes of these distinct phenotypes. Using H-2 congenic mice, we show that the genetic basis for the varied responses between these two strains is independent of the H-2 locus and T cell precursor frequency. C57BL/6 mice treated with costimulation blockade are able to generate allospecific CTL- and IFN-γ-producing T cells within 3–4 wk posttransplant, whereas mice with a C3H background generate neither CTL- nor IFN-γ-producing cells. Thus, differences appear to be in the generation of the immune response and not T cell homing. Strain differences in costimulation blockade-induced hyporesponsiveness persist in the absence of CD4+ T cells, implying a direct effect on CD8+ T cells. We demonstrate that genetic differences are important in cells of hemopoietic origin and that the costimulation blockade-resistant phenotype is dominant. Analysis of BXH recombinant inbred strains indicates that multiple loci contribute to the phenotype, and that the blockade resistance loci are preliminarily linked to 17 markers on four chromosomes. We conclude that strain variation in allograft MSTs following CD40/CD28 blockade results from the ability of CD8+ T cells in some strains to use alternative modes of costimulation to mount an effective alloresponse.

FasL is not required for the establishment of costimulation blockade induced hyporesponsiveness, but rather appears to be required for normal costimulation blockade resistant rejection. Fas expression is not critical for costimulation blockade resistant rejection, suggesting that fasL may be interacting with other receptors. Further, it appears that CD4+ cells are important in the maintenance of allograft protection induced by costimulation blockade in this model.

African Americans are disproportionately affected by HIV and socio-structural barriers that impact antiretroviral (ART) adherence. Two-way text-messaging interventions have shown promise in supporting adherence in US studies of mostly White people living with HIV (PLWH). However, culturally-appropriate tailoring is necessary to maximize intervention effectiveness among other racial/ethnic groups. Thus, to refine an existing text-messaging intervention, we examined barriers and facilitators to ART adherence among African Americans and perspectives on features to integrate into the extant intervention. Three focus groups, two with African American PLWH (n = 5 and n = 7) and one with providers of care (n = 11) were conducted; transcripts of audio-recordings were thematically analyzed. Adherence supports operated at individual, interpersonal, and structural/environmental levels (e.g., using reminders and pill organizers, wanting to protect partners from HIV, and positive interactions with providers). Adherence barriers also operated at multiple ecological levels (e.g., poor mental health, fear of disclosure of HIV status, and unstable housing). Participant-suggested features for refinement included: i) matching content to participants' comfort with receiving messages referencing HIV or medication-taking, ii) culturally-tailoring content for African Americans, iii) tracking adherence, and iv) encouraging adherence interactions between patients and providers. Feedback from both patients and providers is foundational to designing effective ART interventions among African American PLWH.