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1.
J Immunol ; 204(3): 644-659, 2020 02 01.
Article in English | MEDLINE | ID: mdl-31862711

ABSTRACT

Tuberculosis (TB), caused by Mycobacterium tuberculosis, continues to be a major global health problem. Lung granulomas are organized structures of host immune cells that function to contain the bacteria. Cytokine expression is a critical component of the protective immune response, but inappropriate cytokine expression can exacerbate TB. Although the importance of proinflammatory cytokines in controlling M. tuberculosis infection has been established, the effects of anti-inflammatory cytokines, such as IL-10, in TB are less well understood. To investigate the role of IL-10, we used an Ab to neutralize IL-10 in cynomolgus macaques during M. tuberculosis infection. Anti-IL-10-treated nonhuman primates had similar overall disease outcomes compared with untreated control nonhuman primates, but there were immunological changes in granulomas and lymph nodes from anti-IL-10-treated animals. There was less thoracic inflammation and increased cytokine production in lung granulomas and lymph nodes from IL-10-neutralized animals at 3-4 wk postinfection compared with control animals. At 8 wk postinfection, lung granulomas from IL-10-neutralized animals had reduced cytokine production but increased fibrosis relative to control animals. Although these immunological changes did not affect the overall disease burden during the first 8 wk of infection, we paired computational modeling to explore late infection dynamics. Our findings support that early changes occurring in the absence of IL-10 may lead to better bacterial control later during infection. These unique datasets provide insight into the contribution of IL-10 to the immunological balance necessary for granulomas to control bacterial burden and disease pathology in M. tuberculosis infection.


Subject(s)
Granuloma/immunology , Inflammation/immunology , Interleukin-10/metabolism , Lung/pathology , Lymph Nodes/immunology , Mycobacterium tuberculosis/physiology , Tuberculosis/immunology , Animals , Antibodies, Neutralizing/metabolism , Cells, Cultured , Disease Models, Animal , Humans , Immunity , Lung/immunology , Macaca fascicularis , Pulmonary Fibrosis
2.
Clin Transplant ; 35(8): e14369, 2021 08.
Article in English | MEDLINE | ID: mdl-34021521

ABSTRACT

Rabbit antithymocyte globulin (RATG) preparations are widely used in transplantation. They are developed in vivo against thymocytes and contain polyclonal antibodies specific for myriad cellular targets. The rhesus monkey is commonly used as a preclinical transplant model, but the fidelity of commercially available human-specific RATGs to anticipate the effects of RATGs in rhesus has not been established. We therefore developed two rhesus-specific ATGs (rhATG) and compared them to human-specific RATG (huATG, Thymoglobulin® ) in rhesus monkeys, assessing the magnitude and phenotype of depletion peripherally and in lymph nodes. Four primates were assigned to each group and received 20 mg/kg of drug. Depletion, repopulation, and changes in lymphocyte subsets were evaluated in peripheral blood and lymph nodes by flow cytometry over four months. We observed similar qualitative changes in lymphocyte subsets, but a generally more profound depletion with huATG compared to either rhATG. Peripheral homeostatic proliferation rather than thymic output was the major mechanism for repopulation with all RATGs. Repopulation was slower but qualitatively similar when examining RATGs in additional animals receiving concomitant chronic immunosuppression. Depletional induction is similar to human- and rhesus-specific RATGs in rhesus macaques. Both rhesus- and human-specific agents appear appropriate for preclinical modeling of clinical RATG use.


Subject(s)
Antilymphocyte Serum , Animals , Flow Cytometry , Humans , Macaca mulatta
3.
Am J Transplant ; 20(1): 298-305, 2020 01.
Article in English | MEDLINE | ID: mdl-31430418

ABSTRACT

The antagonistic anti-CD40 antibody, 2C10, and its recombinant primate derivative, 2C10R4, are potent immunosuppressive antibodies whose utility in allo- and xenotransplantation have been demonstrated in nonhuman primate studies. In this study, we defined the 2C10 binding epitope and found only slight differences in affinity of 2C10 for CD40 derived from four primate species. Staining of truncation mutants mapped the 2C10 binding epitope to the N-terminal portion of CD40. Alanine scanning mutagenesis of the first 60 residues in the CD40 ectodomain highlighted key amino acids important for binding of 2C10 and for binding of the noncross-blocking anti-CD40 antibodies 3A8 and 5D12. All four 2C10-binding residues defined by mutagenesis clustered near the membrane-distal tip of CD40 and partially overlap the CD154 binding surface. In contrast, the overlapping 3A8 and 5D12 epitopes map to an opposing surface away from the CD154 binding domain. This biochemical characterization of 2C10 confirms the validity of nonhuman primate studies in the translation of this therapeutic antibody and provides insight its mechanism of action.


Subject(s)
Antibodies, Monoclonal/metabolism , CD40 Antigens/metabolism , CD40 Ligand/metabolism , Epitopes/metabolism , Amino Acid Sequence , Animals , Antibodies, Monoclonal/chemistry , Antibodies, Monoclonal/genetics , Antibodies, Monoclonal/immunology , CD40 Antigens/chemistry , CD40 Antigens/genetics , CD40 Antigens/immunology , CD40 Ligand/chemistry , CD40 Ligand/genetics , CD40 Ligand/immunology , Epitopes/chemistry , Epitopes/genetics , Epitopes/immunology , Humans , Macaca mulatta , Mutation , Protein Conformation , Sequence Homology, Amino Acid
4.
Int J Equity Health ; 19(1): 216, 2020 12 09.
Article in English | MEDLINE | ID: mdl-33298093

ABSTRACT

BACKGROUND: While equity is a central concern in promoting Universal Health Coverage (UHC), the impact of social exclusion on equity in UHC remains underexplored. This paper examines challenges faced by socially excluded populations, with an emphasis on Indigenous peoples, to receive UHC in Latin America. We argue that social exclusion can have negative effects on health systems and can undermine progress towards UHC. We examine two case studies, one in Guatemala and one in Peru, involving citizen-led accountability initiatives that aim to identify and address problems with health care services for socially excluded groups. The case studies reveal how social exclusion can affect equity in UHC. METHODS: In-depth analysis was conducted of all peer reviewed articles published between 2015 and 2019 on the two cases (11 in total), and two non-peer reviewed reports published over the same period. In addition, two of the three authors contributed their first-hand knowledge gathered through practitioner involvement with the citizen-led initiatives examined in the two cases. The analysis sought to identify and compare challenges faced by socially excluded Indigenous populations to receive UHC in the two cases. RESULTS: Citizen-led accountability initiatives in Guatemala and Peru reveal very similar patterns of serious deficiencies that undermine efforts towards the realization of Universal Health Coverage in both countries. In each case, the socially excluded populations are served by a dysfunctional publicly provided health system marked by gaps and often invisible barriers. The cases suggest that, while funding and social rights to coverage have expanded, marginalized populations in Guatemala and Peru still do not receive either the health care services or the protection against financial hardship promised by health systems in each country. In both cases, the dysfunctional character of the system remains in place, undermining progress towards UHC. CONCLUSIONS: We conclude that efforts to promote UHC cannot stop at increasing health systems financing. In addition, these efforts need to contend with the deeper challenges of democratizing state institutions, including health systems, involved in marginalizing and excluding certain population groups. This includes stronger accountability systems within public institutions. More inclusive accountability mechanisms are an important step in promoting equitable progress towards UHC.


Subject(s)
Patient Rights , Social Isolation , Social Responsibility , Universal Health Insurance/organization & administration , Delivery of Health Care/economics , Guatemala , Health Equity , Healthcare Disparities , Humans , Peru
5.
BMC Health Serv Res ; 20(1): 416, 2020 May 13.
Article in English | MEDLINE | ID: mdl-32404089

ABSTRACT

BACKGROUND: Citizen-led accountability initiatives are a critical strategy for redressing the causes of health inequalities and promoting better health system governance. A growing body of evidence points to the need for putting power relations at the forefront of understanding and operationalizing citizen-led accountability, rather than technical tools and best practices. In this study, we apply a network lens to the question of how initiatives build collective power to redress health system failures affecting marginalized communities in three municipalities in Guatemala. METHODS: Network mapping and interpretive discussions were used to examine relational qualities of citizen-led initiatives' networks and explore the resources they offer for mobilizing action and influencing health accountability. Participants in the municipal-level initiatives responded to a social network analysis questionnaire focused on their ties of communication and collaboration with other initiative participants and their interactions with authorities regarding health system problems. Discussions with participants about the maps generated enriched our view of what the ties represented and their history of collective action and also provided space for planning action to strengthen their networks. RESULTS: Our findings indicate that network qualities like cohesiveness and centralization reflected the initiative participants' agency in adapting to their sociopolitical context, and participants' social positions were a key resource in providing connection to a broad base of support for mobilizing collective action to document health service deficiencies and advocate for solutions. Their legitimacy as "representatives of the people" enabled them to engage with authorities from a bolstered position of power, and their iterative interactions with authorities further contributed to develop their advocacy capabilities and resulted in accountability gains. CONCLUSIONS: Our study provided evidence to counter the tendency to underestimate the assets and capabilities that marginalized citizens have for building power, and affirmed the idea that best-fit, with-the-grain approaches are well-suited for highly unequal settings characterized by weak governance. Efforts to support and understand change processes in citizen-led initiatives should include focus on adaptive network building to enable contextually-embedded approaches that leverage the collective power of the users of health services and grassroots leaders on the frontlines of accountability.


Subject(s)
Community Networks/organization & administration , Community Participation , Health Services , Social Responsibility , Guatemala , Humans
6.
Int J Equity Health ; 16(1): 26, 2017 02 21.
Article in English | MEDLINE | ID: mdl-28219429

ABSTRACT

The 400 million indigenous people worldwide represent a wealth of linguistic and cultural diversity, as well as traditional knowledge and sustainable practices that are invaluable resources for human development. However, indigenous people remain on the margins of society in high, middle and low-income countries, and they bear a disproportionate burden of poverty, disease, and mortality compared to the general population. These inequalities have persisted, and in some countries have even worsened, despite the overall improvements in health indicators in relation to the 15-year push to meet the Millennium Development Goals. As we enter the Sustainable Development Goals (SDGs) era, there is growing consensus that efforts to achieve Universal Health Coverage (UHC) and promote sustainable development should be guided by the moral imperative to improve equity. To achieve this, we need to move beyond the reductionist tendency to frame indigenous health as a problem of poor health indicators to be solved through targeted service delivery tactics and move towards holistic, integrated approaches that address the causes of inequalities both inside and outside the health sector. To meet the challenge of engaging with the conditions underlying inequalities and promoting transformational change, equity-oriented research and practice in the field of indigenous health requires: engaging power, context-adapted strategies to improve service delivery, and mobilizing networks of collective action. The application of systems thinking approaches offers a pathway for the evolution of equity-oriented research and practice in collaborative, politically informed and mutually enhancing efforts to understand and transform the systems that generate and reproduce inequities in indigenous health. These approaches hold the potential to strengthen practice through the development of more nuanced, context-sensitive strategies for redressing power imbalances, reshaping the service delivery environment and fostering the dynamics of collective action for political reform.


Subject(s)
Delivery of Health Care/standards , Health Services, Indigenous/standards , Healthcare Disparities/standards , Quality Improvement/standards , Universal Health Insurance/standards , Cultural Diversity , Humans , Poverty , Socioeconomic Factors
7.
Int J Equity Health ; 15: 77, 2016 May 13.
Article in English | MEDLINE | ID: mdl-27177690

ABSTRACT

BACKGROUND: Health inequalities disproportionally affect indigenous people in Guatemala. Previous studies have noted that the disadvantageous situation of indigenous people is the result of complex and structural elements such as social exclusion, racism and discrimination. These elements need to be addressed in order to tackle the social determinants of health. This research was part of a larger participatory collaboration between Centro de Estudios para la Equidad y Gobernanza en los Servicios de Salud (CEGSS) and community based organizations aiming to implement social accountability in rural indigenous municipalities of Guatemala. Discrimination while seeking health care services in public facilities was ranked among the top three problems by communities and that should be addressed in the social accountability intervention. This study aimed to understand and categorize the episodes of discrimination as reported by indigenous communities. METHODS: A participatory approach was used, involving CEGSS's researchers and field staff and community leaders. One focus group in one rural village of 13 different municipalities was implemented. Focus groups were aimed at identifying instances of mistreatment in health care services and documenting the account of those who were affected or who witnessed them. All of the 132 obtained episodes were transcribed and scrutinized using a thematic analysis. RESULTS: Episodes described by participants ranged from indifference to violence (psychological, symbolic, and physical), including coercion, mockery, deception and racism. Different expressions of discrimination and mistreatment associated to poverty, language barriers, gender, ethnicity and social class were narrated by participants. CONCLUSIONS: Addressing mistreatment in public health settings will involve tackling the prevalent forms of discrimination, including racism. This will likely require profound, complex and sustained interventions at the programmatic and policy levels beyond the strict realm of public health services. Future studies should assess the magnitude of the occurrence of episodes of maltreatment and racism within indigenous areas and also explore the providers' perceptions about the problem.


Subject(s)
Population Groups/ethnology , Quality of Health Care/standards , Racism/trends , Female , Focus Groups , Guatemala/ethnology , Humans , Male , Population Groups/psychology , Qualitative Research , Rural Population
8.
Hum Resour Health ; 13: 82, 2015 Oct 13.
Article in English | MEDLINE | ID: mdl-26462768

ABSTRACT

Appropriate deployment or posting and transfer (P&T) of health workers - placing the right people in the right positions at the right time - lies at the heart of fostering communities' faith in government health services and cementing the role of the health system as a core social institution. The authors of this paper have been involved in an ongoing transnational dialogue about P&T practices and determinants. This dialogue seeks to call attention to the importance of P&T as a health system function; to urge donors and policy-makers working in health systems, HRH and public administration governance to consider how to address issues around P&T; and to suggest avenues and approaches to research. P&T is a vexed and unresolved issue in many low- and middle-income countries that requires, above all, political commitment to improving public sector services and to new thinking and research. It holds promise as a focal point for inter-disciplinary collaboration in research and implementation that can inform other areas in HRH and health systems strengthening. Innovative social science and management theorizing, and iterative, locally driven interventions that focus on establishing transparent professional norms and building the credibility of government administration, including the health services, are likely the way forward.


Subject(s)
Government , Health Personnel , Health Services Accessibility , Health Services , Personnel Management , Public Sector , Trust , Developing Countries , Health Services/standards , Humans , Social Responsibility , Workforce
9.
Int J Equity Health ; 13: 57, 2014 Oct 10.
Article in English | MEDLINE | ID: mdl-25301549

ABSTRACT

INTRODUCTION: The United Nations presented a set of Millennium Development Goals that aimed to improve social and economic development and eradicate poverty by 2015. Most low and middle-income countries will not meet these goals and today there is a need to set new development agenda, especially when it comes to health. The paper presents the findings from a community consultation process carried out within the Goals and Governance for Global Health (GO4Health) research consortium in Guatemala, which aims to identify community needs and expectations around public policies and health services. METHODS: Through a participative and open consultation process with experts, civil society organizations and members of the research team, the municipalities of Tectitan and Santa Maria Nebaj were selected. A community consultation process was undertaken with community members and community leaders. Group discussions and in-depth interviews were conducted and later analyzed using thematic analysis, a qualitative method that can be used to analyze data in a way that allows for the identification of recurrent patterns that can be grouped into categories and themes, was used. FINDINGS: Following the Go4Health framework's domains for understanding health-related needs, the five themes identified were health, social determinants of health, essential health needs and their provision, roles and responsibilities of relevant stakeholders and community participation in decision-making. Participants reported high levels of discrimination related to ethnicity, to being poor and to living in rural areas. Ethnicity played a major role in how community members feel they are cared for in the health system. CONCLUSION: Achieving health goals in a context of deep-rooted inequality and marginalization requires going beyond the simple expansion of health services and working with developing trusting relationships between health service providers and community members. Involving community members in decision-making processes that shape policies will contribute to a larger process of community empowerment and democratization. Still, findings from the region show that tackling these issues may prove complicated and require going beyond the health system, as this lack of trust and discrimination has permeated to all public policies that deal with indigenous and rural populations.


Subject(s)
Global Health , Goals , Health Services Needs and Demand , Health Status Disparities , Social Discrimination , Focus Groups , Guatemala , Humans , Population Groups , Qualitative Research , Rural Population , Surveys and Questionnaires
10.
Lancet ; 390(10095): 647-648, 2017 08 12.
Article in English | MEDLINE | ID: mdl-28816133
11.
BMJ Glob Health ; 7(5)2022 05.
Article in English | MEDLINE | ID: mdl-35508334

ABSTRACT

Growing interest in how marginalised citizens can leverage countervailing power to make health systems more inclusive and equitable points to the need for politicised frameworks for examining bottom-up accountability initiatives. This study explores how political capabilities are manifested in the actions and strategies of Indigenous grassroots leaders of health accountability initiatives in rural Guatemala. Qualitative data were gathered through group discussions and interviews with initiative leaders (called defenders of the right to health) and initiative collaborators in three municipalities. Analysis was oriented by three dimensions of political capabilities proposed for evaluating the longer-term value of participatory development initiatives: political learning, reshaping networks and patterns of representation. Our findings indicated that the defenders' political learning began with actionable knowledge about defending the right to health and citizen participation. The defenders used their understanding of local norms to build trust with remote Indigenous communities and influence them to participate in monitoring to attempt to hold the state accountable for the discriminatory and deficient healthcare they received. Network reshaping was focused on broadening their base of support. Their leadership strategies enabled them to work with other grassroots leaders and access resources that would expand their reach in collective action and lend them more influence representing their problems beyond the local level. Patterns of representing their interests with a range of local and regional authorities indicated they had gained confidence and credibility through their evolving capability to navigate the political landscape and seek the right authority based on the situation. Our results affirm the critical importance of sustained, long-term processes of engagement with marginalised communities and representatives of the state to enable grassroots leaders of accountability initiatives to develop the capabilities needed to mobilise collective action, shift the terms of interaction with the state and build more equitable health systems.


Subject(s)
Rural Population , Social Responsibility , Delivery of Health Care , Guatemala , Humans , Leadership
12.
PLOS Glob Public Health ; 2(9): e0000220, 2022.
Article in English | MEDLINE | ID: mdl-36962482

ABSTRACT

The financing of surgical care for children in low- and middle-income countries (LMICs) remains challenging and may restrict adherence to universal health coverage (UHC) frameworks. Our aims were to describe Guatemala's national pediatric surgical financing structure, to identify financing challenges, and to develop recommendations to improve the financing of surgical care for children. We conducted a qualitative study of the financing of surgical care for children in Guatemala's public health system with key informant interviews (n = 20) with experts in the medical, financial, and political health sectors. We used this data to generate recommendations to improve surgical care financing for children. We identified several systemic challenges to the financing of surgical care for children, including passive purchasing structures, complex political contexts, health system fragmentation, widespread use of informal fees for surgical services, and lack of earmarked funding for surgical care. Patient and provider challenges include lack of provider input in non-personnel funding decisions, and patients functioning as both financing agents and beneficiaries in the same financing stream. Key recommendations include reducing health finance system fragmentation through resource pooling, increasing earmarked funding for surgical care with quantifiable outcome measures, engagement with clinical providers in non-personnel budgetary decision-making, and use of innovative financing instruments such as resource pooling. Surgical financing for children in Guatemala requires substantial remodeling to increase access to timely, affordable, and safe surgical care and improve alignment with Guatemala's UHC scheme.

13.
J Clin Invest ; 132(10)2022 05 16.
Article in English | MEDLINE | ID: mdl-35316218

ABSTRACT

Proliferation of latently infected CD4+ T cells with replication-competent proviruses is an important mechanism contributing to HIV persistence during antiretroviral therapy (ART). One approach to targeting this latent cell expansion is to inhibit mTOR, a regulatory kinase involved with cell growth, metabolism, and proliferation. Here, we determined the effects of chronic mTOR inhibition with rapamycin with or without T cell activation in SIV-infected rhesus macaques (RMs) on ART. Rapamycin perturbed the expression of multiple genes and signaling pathways important for cellular proliferation and substantially decreased the frequency of proliferating CD4+ memory T cells (TM cells) in blood and tissues. However, levels of cell-associated SIV DNA and SIV RNA were not markedly different between rapamycin-treated RMs and controls during ART. T cell activation with an anti-CD3LALA antibody induced increases in SIV RNA in plasma of RMs on rapamycin, consistent with SIV production. However, upon ART cessation, both rapamycin and CD3LALA-treated and control-treated RMs rebounded in less than 12 days, with no difference in the time to viral rebound or post-ART viral load set points. These results indicate that, while rapamycin can decrease the proliferation of CD4+ TM cells, chronic mTOR inhibition alone or in combination with T cell activation was not sufficient to disrupt the stability of the SIV reservoir.


Subject(s)
HIV Infections , Simian Acquired Immunodeficiency Syndrome , Simian Immunodeficiency Virus , Animals , Anti-Retroviral Agents/pharmacology , Anti-Retroviral Agents/therapeutic use , CD4-Positive T-Lymphocytes , Cell Proliferation , HIV Infections/drug therapy , Macaca mulatta/genetics , RNA , Sirolimus/pharmacology , TOR Serine-Threonine Kinases/genetics , TOR Serine-Threonine Kinases/pharmacology , Viral Load , Virus Replication
14.
Malar J ; 10: 379, 2011 Dec 20.
Article in English | MEDLINE | ID: mdl-22185638

ABSTRACT

BACKGROUND: The objective of this study was to implement a rapid assessment of the performance of four malaria control strategies (indoor spraying, insecticide-treated bed nets, timely diagnosis, and artemisinin-based combination therapy) using adequacy criteria. The assessment was carried out in five countries of the Amazon subregion (Bolivia, Colombia, Ecuador, Guyana, and Peru). METHODS: A list of criteria in three areas was created for each of the four strategies: preliminary research that supports the design and adaptation of the control strategies, coverage of the control strategies and quality of the implementation of the strategies. The criteria were selected by the research team and based on the technical guidelines established by the World Health Organization. Each criterion included in the four lists was graded relative to whether evidence exists that the criterion is satisfied (value 1), not satisfied (value 0) or partially satisfied (value 0.5). The values obtained were added and reported according to a scale of three implementation categories: adequate, intermediate and deficient. RESULTS: Implementation of residual indoor spraying and timely diagnosis was adequate in one country and intermediate or deficient in the rest. Insecticide-treated bed nets ranged between deficient and intermediate in all the countries, while implementation of artemisinin-based combination therapy (ACT) was adequate in three countries and intermediate in the other two countries evaluated. CONCLUSIONS: Although ACT is the strategy with the better implementation in all countries, major gaps exist in implementation of the other three malaria control strategies in terms of technical criteria, coverage and quality desired. The countries must implement action plans to close the gaps in the various criteria and thereby improve the performance of the interventions. The assessment tools developed, based on adequacy criteria, are considered useful for a rapid assessment by malaria control authorities in the different countries.


Subject(s)
Disease Eradication/methods , Malaria/prevention & control , Program Evaluation/methods , Antimalarials/therapeutic use , Artemisinins/therapeutic use , Bolivia/epidemiology , Colombia/epidemiology , Data Collection , Disease Transmission, Infectious/prevention & control , Drug Combinations , Ecuador/epidemiology , Guyana/epidemiology , Humans , Insecticide-Treated Bednets/statistics & numerical data , Insecticides/administration & dosage , Malaria/diagnosis , Malaria/drug therapy , Malaria/epidemiology , Mosquito Control/methods , Peru/epidemiology , Plasmodium/pathogenicity
15.
Front Immunol ; 12: 660900, 2021.
Article in English | MEDLINE | ID: mdl-34149698

ABSTRACT

Background: In transplantation, plasmapheresis and IVIg provide the mainstay of treatment directed at reducing or removing circulating donor-specific antibody (DSA), yet both have limitations. We sought to test the efficacy of targeting the IgG recycling mechanism of the neonatal Fc receptor (FcRn) using anti-FcRn mAb therapy in a sensitized non-human primate (NHP) model, as a pharmacological means of lowering DSA. Methods: Six (6) rhesus macaque monkeys, previously sensitized by skin transplantation, received a single dose of 30mg/kg anti-RhFcRn IV, and effects on total IgG, as well as DSA IgG, were measured, in addition to IgM and protective immunity. Subsequently, 60mg/kg IV was given in the setting of kidney transplantation from skin graft donors. Kidney transplant recipients received RhATG, and tacrolimus, MMF, and steroid for maintenance immunosuppression. Results: Circulating total IgG was reduced from a baseline 100% on D0 to 32.0% (mean, SD ± 10.6) on d4 post infusion (p<0.05), while using a DSA assay. T-cell flow cross match (TFXM) was reduced to 40.6±12.5% of baseline, and B-cell FXCM to 52.2±19.3%. Circulating total IgM and DSA IgM were unaffected by treatment. Pathogen-specific antibodies (anti-gB and anti-tetanus toxin IgG) were significantly reduced for 14d post infusion. Post-transplant, circulating IgG responded to anti-FcRn mAb treatment, but DSA increased rapidly. Conclusion: Targeting the FcRn-mediated recycling of IgG is an effective means of lowering circulating donor-specific IgG in the sensitized recipient, although in the setting of organ transplantation mechanisms of rapid antibody rise post-transplant remains unaffected.


Subject(s)
Histocompatibility Antigens Class I/immunology , Immunoglobulin G/immunology , Immunoglobulins, Intravenous/therapeutic use , Isoantibodies/immunology , Receptors, Fc/immunology , Tissue Donors , Animals , Antibodies, Monoclonal/therapeutic use , Graft Rejection/immunology , Graft Rejection/prevention & control , Graft Survival , Histocompatibility Testing , Immunoglobulin G/blood , Immunosuppression Therapy , Immunosuppressive Agents/administration & dosage , Kidney Transplantation , Macaca mulatta , Male , Models, Animal
16.
Front Immunol ; 12: 657424, 2021.
Article in English | MEDLINE | ID: mdl-33796119

ABSTRACT

The antiviral properties of broadly neutralizing antibodies against HIV are well-documented but no vaccine is currently able to elicit protective titers of these responses in primates. While current vaccine modalities can readily induce non-neutralizing antibodies against simian immunodeficiency virus (SIV) and HIV, the ability of these responses to restrict lentivirus transmission and replication remains controversial. Here, we investigated the antiviral properties of non-neutralizing antibodies in a group of Indian rhesus macaques (RMs) that were vaccinated with vif, rev, tat, nef, and env, as part of a previous study conducted by our group. These animals manifested rapid and durable control of viral replication to below detection limits shortly after SIVmac239 infection. Although these animals had no serological neutralizing activity against SIVmac239 prior to infection, their pre-challenge titers of Env-binding antibodies correlated with control of viral replication. To assess the contribution of anti-Env humoral immune responses to virologic control in two of these animals, we transiently depleted their circulating antibodies via extracorporeal plasma immunoadsorption and inhibition of IgG recycling through antibody-mediated blockade of the neonatal Fc receptor. These procedures reduced Ig serum concentrations by up to 80% and temporarily induced SIVmac239 replication in these animals. Next, we transferred purified total Ig from the rapid controllers into six vaccinated RMs one day before intrarectal challenge with SIVmac239. Although recipients of the hyperimmune anti-SIV Ig fraction were not protected from infection, their peak and chronic phase viral loads were significantly lower than those in concurrent unvaccinated control animals. Together, our results suggest that non-neutralizing Abs may play a role in the suppression of SIVmac239 viremia.


Subject(s)
Antibodies, Viral/immunology , Host-Pathogen Interactions/immunology , Simian Acquired Immunodeficiency Syndrome/immunology , Simian Acquired Immunodeficiency Syndrome/virology , Simian Immunodeficiency Virus/immunology , Viremia/immunology , Viremia/virology , Animals , Antibodies, Viral/blood , Biomarkers , Genotype , Histocompatibility Antigens Class I , Immunoglobulin G/blood , Immunoglobulin G/immunology , Macaca mulatta , Receptors, Fc , Simian Immunodeficiency Virus/genetics , Viral Load
17.
Health Hum Rights ; 22(1): 199-207, 2020 Jun.
Article in English | MEDLINE | ID: mdl-32669801

ABSTRACT

We propose that a Right to Health Capacity Fund (R2HCF) be created as a central institution of a reimagined global health architecture developed in the aftermath of the COVID-19 pandemic. Such a fund would help ensure the strong health systems required to prevent disease outbreaks from becoming devastating global pandemics, while ensuring genuinely universal health coverage that would encompass even the most marginalized populations. The R2HCF's mission would be to promote inclusive participation, equality, and accountability for advancing the right to health. The fund would focus its resources on civil society organizations, supporting their advocacy and strengthening mechanisms for accountability and participation. We propose an initial annual target of US$500 million for the fund, adjusted based on needs assessments. Such a financing level would be both achievable and transformative, given the limited right to health funding presently and the demonstrated potential of right to health initiatives to strengthen health systems and meet the health needs of marginalized populations-and enable these populations to be treated with dignity. We call for a civil society-led multi-stakeholder process to further conceptualize, and then launch, an R2HCF, helping create a world where, whether during a health emergency or in ordinary times, no one is left behind.


Subject(s)
Communicable Disease Control/organization & administration , Coronavirus Infections/epidemiology , Financing, Organized/organization & administration , Global Health , International Cooperation , Pneumonia, Viral/epidemiology , Betacoronavirus , COVID-19 , Capacity Building/organization & administration , Communicable Disease Control/economics , Health Priorities/organization & administration , Humans , Pandemics , SARS-CoV-2
18.
Health Hum Rights ; 11(1): 37-48, 2009.
Article in English | MEDLINE | ID: mdl-20845849

ABSTRACT

Social participation has been understood in many different ways, and there are even typologies classifying participation by the degree of a population's control in decision making. Participation can vary from a symbolic act, which does not involve decision making, to processes in which it constitutes the principal tool for redistributing power within a population. This article argues that analyzing social participation from a perspective of power relations requires knowledge of the historical, social, and economic processes that have characterized the social relations in a specific context. Applying such an analysis to Guatemala reveals asymmetrical power relations characterized by a long history of repression and political violence. The armed conflict during the second half of the 20th century had devastating consequences for a large portion of the population as well as the country's social leadership. The ongoing violence resulted in negative psychosocial effects among the population, including mistrust toward institutions and low levels of social and political participation. Although Guatemala made progress in creating spaces for social participation in public policy after signing the Peace Accords in 1996, the country still faces after-effects of the conflict. One important task for the organizations that work in the field of health and the right to health is to help regenerate the social fabric and to rebuild trust between the state and its citizens. Such regeneration involves helping the population gain the skills, knowledge, and information needed in order to participate in and affect formal political processes that are decided and promoted by various public entities, such as the legislative and executive branches, municipal governments, and political parties. This process also applies to other groups that build citizenship through participation, such as neighborhood organizations and school and health committees.


Subject(s)
Community Participation/methods , Delivery of Health Care/organization & administration , Human Rights , Politics , Violence , Community Participation/psychology , Dissent and Disputes , Guatemala , Humans , Power, Psychological , Public Policy
20.
Health Hum Rights ; 20(2): 169-184, 2018 Dec.
Article in English | MEDLINE | ID: mdl-30568411

ABSTRACT

Information and Communication Technology (ICT) may facilitate the collection and dissemination of citizen-generated data to enhance governmental accountability for the fulfillment of the right to health. The aim of this multiple case study research was to distill considerations related to the implementation of ICT and health accountability projects, describe the added operational value of ICT tools (as compared to similar projects that do not use ICT), and make preliminary statements regarding government responsiveness to accountability demands through ICT projects. In all three projects, the need for relationship building, continuous community engagement and technical support, and training for volunteers or service users was identified. Government responsiveness to the data varied, suggesting that political will is lacking in certain contexts. Despite these challenges, ICT initiatives provided an easy, accessible, and low-risk platform for reporting violations and demanding accountability from service providers and decision-makers. ICT-enabled citizen generated data can add significant operational value and some political value to project activities and goals, and may affect systems change when it is part of a broad-based, multi-level civil societal and governmental effort to improve health care quality.


Subject(s)
Communication , Community Participation , Information Technology , Social Responsibility , Delivery of Health Care , Developing Countries , Guatemala , Health Personnel , Human Rights , Humans , India , Models, Organizational , Quality of Health Care
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