About

Laurence U Buxbaum, MD, Ph.D., is a Clinical Associate Professor of Medicine in the Department of Medicine (Infectious Diseases) at the Perelman School of Medicine, University of Pennsylvania. His research expertise centers on the immunology of chronic Leishmania infection, with a focus on understanding the immune mechanisms involved in parasite-host interactions. His research interests include immunoparasitology, the role of IL-10 responses, IgG and FcgammaR interactions, and parasite immunology, particularly in the context of Leishmania mexicana and related species. Dr. Buxbaum's work aims to elucidate why certain Leishmania strains cause non-healing disease while others heal, investigating the cytokine IL-10's role in suppressing protective immune responses and the cellular sources of IL-10. His studies also explore the involvement of FcγR and IgG isotypes in disease progression, as well as the potential of glycolipids as surface targets of IgG. His research contributes to a broader understanding of cell-mediated immunity in parasitic infections, which may provide insights into other intracellular pathogens such as tuberculosis, toxoplasmosis, and HIV.

Research topics

• Biology
• Immunology
• Microbiology
• Biochemistry
• Virology

Selected publications

• Association of Costs and Days at Home With Transfer Hospital in Home

  JAMA Network Open · 2021-06-29 · 24 citations

  articleOpen access

  Importance: New Centers for Medicare & Medicaid Services waivers created a payment mechanism for hospital at home services. Although it is well established that direct admission to hospital at home from the community as a substitute for hospital care provides superior outcomes and lower cost, the effectiveness of transfer hospital at home-that is, completing hospitalization at home-is unclear. Objective: To evaluate the outcomes of the transfer component of a Veterans Affairs (VA) Hospital in Home program (T-HIH), taking advantage of natural geographical limitations in a program's service area. Design, Setting, and Participants: In this quality improvement study, T-HIH was offered to veterans residing in Philadelphia, Pennsylvania, and their outcomes were compared with those of propensity-matched veterans residing in adjacent Camden, New Jersey, who were admitted to the VA hospital from 2012 to 2018. Data analysis was performed from October 2019 to May 2020. Intervention: Enrollment in the T-HIH program. Main Outcomes and Measures: The main outcomes were hospital length of stay, 30-day and 90-day readmissions, VA direct costs, combined VA and Medicare costs, mortality, 90-day nursing home use, and days at home after hospital discharge. An intent-to-treat analysis of cost and utilization was performed. Results: A total of 405 veterans (mean [SD] age, 66.7 [0.83] years; 399 men [98.5%]) with medically complex conditions, primarily congestive heart failure and chronic obstructive pulmonary disease exacerbations (mean [SD] hierarchical condition categories score, 3.54 [0.16]), were enrolled. Ten participants could not be matched, so analyses were performed for 395 veterans (all of whom were men), 98 in the T-HIH group and 297 in the control group. For patients in the T-HIH group compared with the control group, length of stay was 20% lower (6.1 vs 7.7 days; difference, 1.6 days; 95% CI, -3.77 to 0.61 days), VA costs were 20% lower (-$5910; 95% CI, -$13 049 to $1229), combined VA and Medicare costs were 22% lower (-$7002; 95% CI, -$14 314 to $309), readmission rates were similar (23.7% vs 23.0%), the numbers of nursing home days were significantly fewer (0.92 vs 7.45 days; difference, -6.5 days; 95% CI, -12.1 to -0.96 days; P = .02), and the number of days at home was 18% higher (81.4 vs 68.8 days; difference, 12.6 days; 95% CI, 3.12 to 22.08 days; P = .01). Conclusions and Relevance: In this study, T-HIH was significantly associated with increased days at home and less nursing home use but was not associated with increased health care system costs.

  PublisherOA PDFDOI

• Modeling the immune system response: an application to leishmaniasis

  Mathematical Biosciences & Engineering · 2019-11-19 · 4 citations

  articleOpen access

  In this paper, we present a mathematical model of the immune response to parasites. The model is a type of predator-prey system in which the parasite serves as the prey and the immune response as the predator. The model idealizes the entire immune response as a single entity although it is comprised of several aspects. Parasite density is captured using logistic growth while the immune response is modeled as a combination of two components, activation by parasite density and an autocatalytic reinforcement process. Analysis of the equilibria of the model demonstrate bifurcations between parasites and immune response arising from the autocatalytic response component. The analysis also points to the steady states associated with disease resolution or persistence in leishmaniasis. Numerical predictions of the model when applied to different cases of Leishmania mexicana are in very close agreement with experimental observations.

  PublisherDOI

• Interleukin-10 from T Cells, but Not Macrophages and Granulocytes, Is Required for Chronic Disease in Leishmania mexicana Infection

  Infection and Immunity · 2015-01-21 · 23 citations

  articleOpen access1st authorCorresponding

  Chronic cutaneous disease of mice caused by the protozoan parasite Leishmania mexicana requires interleukin-10 (IL-10) and FcγRIII (an activating IgG receptor). Macrophages readily secrete IL-10 in response to IgG-coated amastigotes, making macrophages a prime candidate as the critical source of IL-10. However, indirect evidence suggested that macrophage IL-10 is not essential for chronic disease. I now show directly that mice lacking IL-10 from macrophages and granulocytes still have chronic disease, like wild-type C57BL/6 mice. However, T cell-derived IL-10 is required for chronic disease. CD4-cre IL-10flox/flox mice lack IL-10 from T cells (both CD4+ and CD8+) and heal their L. mexicana lesions, with parasite control. I had previously shown that depletion of CD25+ T cells had no effect on chronic disease, and thus, T cells other than CD25+ regulatory T (Treg) cells should be the important source of IL-10. Given that conventional T cells do not express FcγRs, there is likely to be an indirect pathway by which FcγRIII on some other cell engaged by IgG1-amastigote immune complexes induces IL-10 from T cells. Further work is needed to delineate these pathways.

  PublisherOA PDFDOI

• Tongue Fat Infiltration in Obese Versus Lean Zucker Rats

  SLEEP · 2014-05-30 · 36 citations

  articleOpen access

  STUDY OBJECTIVES: Obesity is the most important risk factor for obstructive sleep apnea (OSA), and the effects of obesity may be mediated by tongue fat. Our objective was to examine the effects of obesity on upper airway structures in obese (OBZ) and non-obese (NBZ) Zucker rats. DESIGN: Animal study. SETTING: Academic Medical Center. PARTICIPANTS: OBZ (638.2 ± 39 g; 14.9 ± 1.1 w) and age-matched NBZ Zucker (442.6 ± 37 g, 15.1 ± 1.5 w) rats. INTERVENTIONS: TONGUE FAT AND VOLUME AND WERE ASSESSED USING: in vivo magnetic resonance spectroscopy (MRS), magnetic resonance imaging including Dixon imaging for tongue fat volume, ex vivo biochemistry (fat quantification; triglyceride (mg)/tissue (g), and histology (Oil Red O stain). MEASUREMENTS AND RESULTS: MRS: overall OBZ tongue fat/water ratio was 2.9 times greater than NBZ (P < 0.002) with the anterior OBZ tongue up to 3.3 times greater than NBZ (P < 0.002). Biochemistry: Triglyceride (TG) in the tongue was 4.4 times greater in OBZ versus NBZ (P < 0.0006). TG was greater in OBZ tongue (3.57 ± 1.7 mg/g) than OBZ masseter muscle (0.28 ± 0.1; P < 0.0001) but tongue and masseter TG were not different in NBZ rats (0.82 ± 0.3 versus 0.28 ± 0.1 mg/g, P = 0.67). Dixon fat volume was significantly increased in OBZ (56 ± 15 mm3) versus NBZ (34 ± 5 mm3, P < 0.004). Histology demonstrated a greater degree of intracellular muscle fat and extramuscular fat infiltration in OBZ versus NBZ rats. CONCLUSIONS: Genetically obese rats had a large degree of fat infiltration in the tongue compared to both skeletal muscle and tongue tissues of the non-obese age-matched littermates. The significant fat increase and sequestration in the obese tongue may play a role in altered tongue neuromuscular function, tongue stiffness or metabolic function.

  PublisherOA PDFDOI

• IL-10 from T cells, but not macrophages is required for chronic disease in <i>Leishmania mexicana</i> infection (P3328)

  The Journal of Immunology · 2013-05-01

  article1st authorCorresponding

  Abstract Chronic cutaneous disease of mice caused by the protozoan parasite Leishmania mexicana requires IL-10 and FcγRIII (an activating IgG receptor). Macrophages are abundant in lesions and readily secrete IL-10 in response to IgG-coated amastigote stage parasites, making macrophages a prime candidate as the critical source of IL-10. However, both direct and indirect evidence demonstrated that macrophage IL-10 is not essential for chronic disease. Specifically, macrophage-granulocyte specific IL-10-deficient mice have chronic disease identical to wild-type mice. We now show that T cell-derived IL-10 is required for chronic disease. CD4-cre IL-10flox/flox mice lack IL-10 from T cells (both CD4+ and CD8+) and heal their L. mexicana lesions. We had previously shown that depletion of CD25+ T cells had no effect on chronic disease, and thus T cells other than Treg cells should be the important source of IL-10. Given that conventional T cells do not express FcγRs, there is likely to be an indirect pathway by which FcγRIII engagement on some other cell induces IL-10 from T cells. Further work is needed to delineate these pathways.

  PublisherDOI

• Leishmania mexicana Infection Induces IgG to Parasite Surface Glycoinositol Phospholipids that Can Induce IL-10 in Mice and Humans

  PLoS neglected tropical diseases · 2013-05-09 · 19 citations

  articleOpen access1st authorCorresponding

  Infection with the intracellular protozoan parasite Leishmania mexicana causes chronic disease in C57BL/6 mice, in which cutaneous lesions persist for many months with high parasite burdens (10(7)-10(8) parasites). This chronic disease process requires host IL-10 and FcγRIII. When Leishmania amastigotes are released from cells, surface-bound IgG can induce IL-10 and suppress IL-12 production from macrophages. These changes decrease IFN-γ from T cells and nitric oxide production in infected cells, which are both required for Leishmania control. However, antibodies targets and the kinetics of antibody production are unknown. Several groups have been unsuccessful in identifying amastigote surface proteins that bind IgG. We now show that glycoinositol phospholipids (GIPLs) of L. mexicana are recognized by mouse IgG1 by 6 weeks of infection, with a rapid increase between 12 and 16 weeks, consistent with the timing of chronic disease in C57BL/6 mice vs. healing in FcγRIII-deficient mice. A single prominent spot on TLC is recognized by IgG, and the glycolipid is a glycosyl phosphatidylinositol containing a branched mannose structure. We show that the lipid structure of the GIPL (the sn-2 fatty acid) is required for antibody recognition. This GIPL is abundant in L. mexicana amastigotes, rare in stationary-phase promastigotes, and absent in L. major, consistent with a role for antibodies to GIPLs in chronic disease. A mouse monoclonal anti-GIPL IgG recognizes GIPLs on the parasite surface, and induces IL-10 from macrophages. The current work also extends this mouse analysis to humans, finding that L. mexicana-infected humans with localized and diffuse cutaneous leishmaniasis have antibodies that recognize GIPLs, can bind to the surface of amastigotes, and can induce IL-10 from human monocytes. Further characterization of the target glycolipids will have important implications for drug and vaccine development and will elucidate the poorly understood role of glycolipids in the immunology of infections.

  PublisherOA PDFDOI

• IL-10 from macrophages and granulocytes is not required for chronic disease in <i>Leishmania mexicana</i> infection (56.8)

  The Journal of Immunology · 2011-04-01 · 1 citations

  article1st authorCorresponding

  Abstract Chronic disease of mice caused by the protozoan parasite Leishmania mexicana requires IL-10 and FcγRIII. Immune complexes consisting of IgG bound to the surface of Leishmania amastigotes can induce IL-10 and suppress IL-12 production from macrophages in vitro. We have found that IgG1 and IgG2a/c can each efficiently induce IL-10 from macrophages, whereas in vivo, mice that lack IgG1 and have stronger and earlier IgG2a/c responses, are more resistant to L. mexicana infection. This calls into question the crucial role of macrophages as the source of IL-10 required for chronic disease. We now show that tissue-specific IL-10-deficient mice lacking IL-10 from macrophages and granulocytes still have chronic disease similar to WT C57BL/6 mice. These Lyz2-cre-IL-10fl/fl mice clearly lack IL-10 from macrophages as expected, but have a similar course of infection and parasite loads as the WT mice. This shows more directly that macrophage IL-10 is not required for chronic disease and that neutrophils are also not a required source of IL-10. Prior work showed that depletion of CD25+CD4+ T cells also produced no major change in chronic disease and that T cell IL-10 in lymph nodes did not differ in mice that heal (such as FcγRIII KO mice) and those that have chronic disease (WT mice). This leaves an open question as to the important source of IL-10, likely in lesions rather than in the lymph node.

  PublisherDOI

• Eliminating murine norovirus by cross-fostering.

  PubMed · 2011-07-01 · 12 citations

  article1st authorCorresponding

  Murine norovirus (MNV) is a newly discovered and extremely prevalent pathogen of laboratory mouse colonies. MNV causes severe disease in some immunocompromised mouse strains and can cause persistent infections even in immunocompetent mice. Despite the fact that immunocompetent mice are generally asymptomatic, the possibility that MNV infection might alter immune responses makes its eradication a potentially useful goal for many facilities. Initial attempts by others to use a strategy of testing and culling were unsuccessful, whereas complete depopulation and facility decontamination was successful. However, these measures may be impractical, and finding less drastic approaches seemed prudent. Based on a report that cross-fostering of pups from MNV-positive mothers to MNV-negative ones could be successful in experimental MNV infection, we undertook a comprehensive fostering program using Swiss Webster mothers, careful sanitary measures, and fecal PCR testing to eradicate the virus from a mouse colony recently infected with MNV. We successfully decontaminated 17 of 18 (94%) litters and managed to prevent spread when a new MNV-infected mouse strain entered quarantine at our facility. These results suggest that cross-fostering, when performed in a setting of excellent sanitary procedures, may be practical for the large number of mouse facilities in which MNV is endemic.

  Publisher

• IgG1 Is Pathogenic in <i>Leishmania mexicana</i> Infection

  The Journal of Immunology · 2010-10-30 · 39 citations

  articleOpen accessSenior author

  There are >2 million new cases of leishmaniasis annually, and no effective vaccine has been developed to prevent infection. In murine infection, Leishmania mexicana, which lives intracellularly in host macrophages, has developed pathways to hijack host IgG to induce a suppressive IL-10 response through FcγRs, the cell-surface receptors for IgG. To guide vaccine development away from detrimental Ab responses, which can accompany attempts to induce cell-mediated immunity, it is crucial to know which isotypes of IgG are pathogenic in this infection. We found that IgG1 and IgG2a/c induce IL-10 from macrophages in vitro equally well but through different FcγR subtypes: IgG1 through FcγRIII and IgG2a/c through FcγRI primarily, but also through FcγRIII. In sharp contrast, mice lacking IgG1 develop earlier and stronger IgG2a/c, IgG3, and IgM responses to L. mexicana infection and yet are more resistant to the infection. Thus, IgG1, but not IgG2a/c or IgG3, is pathogenic in vivo, in agreement with prior studies indicating that FcγRIII is required for chronic disease. This calls into question the assumption that macrophages, which should secrete IL-10 in response to IgG1 and IgG2a/c immune complexes, are the most important source of IL-10 generated by IgG-FcγR engagement in L. mexicana infection. Further investigations are required to better determine the cell type responsible for this immunosuppressive FcγRIII-induced IL-10 pathway and whether IgG2a/c is protective.

  PublisherOA PDFDOI

• <i>Leishmania mexicana</i> infection induces antibody responses to parasite surface glycolipids that can induce IL-10 and suppress IL-12 from macrophages (37.25)

  The Journal of Immunology · 2010-04-01 · 1 citations

  article1st authorCorresponding

  Abstract Chronic disease of mice caused by the protozoan parasite Leishmania mexicana requires IL-10 and FcγRIII. Immune complexes consisting of IgG bound to the surface of Leishmania amastigotes can induce IL-10 and suppress IL-12 production from macrophages. However, the targets of these antibodies and the kinetics of their production are not known. Several groups have attempted, without success, to identify surface proteins on the amastigote form of the parasite to which IgG can bind. Using ELISA and thin layer chromatography (TLC) immunoblot methods we now show that parasite glycoinositol phospholipids (GIPLs) of L. mexicana are recognized by IgG1 by 6 weeks of infection with a rapid increase between 14-16 wks, consistent with the timing of chronic disease in C57BL/6 mice vs. healing in FcγRIII KO mice. We found that a single prominent spot on TLC is recognized by mouse serum of infected mice and that the glycolipid has a glycosyl phosphatidylinositol (GPI) structure as assessed by GPI-PLC and GPI-PLD susceptibility. Alpha-mannosidase treatment changed the mobility of the recognized glycolipid, indicating that a branched mannose occurs in the structure, but is not required for IgG binding. Further characterization of the target glycolipids will have important implications for vaccine development as well as elucidating the poorly understood role of glycolipids in immunology. Funded by VA Merit, the University of Pennsylvania, and NIH R01-AI081717.

  PublisherDOI

Recent grants

• NIH Grant R01AI081717

  NIH · $1.2M · 2015

• NIH Grant K08AI001805

  NIH · $378k · 2003

Frequent coauthors

• Bolaji N. Thomas

  Rochester Institute of Technology

  14 shared

• Paul T. Englund

  Johns Hopkins University

  13 shared

• Jayne Raper

  The Graduate Center, CUNY

  12 shared

• Ciaran S. Phibbs

  VA Palo Alto Health Care System

  6 shared

• Bruce Kinosian

  University of Pennsylvania

  4 shared

• Fred R. Opperdoes

  de Duve Institute

  4 shared

• Caitlin S. Chan

  Health Services Research & Development

  4 shared

• Karl A. Werbovetz

  The Ohio State University

  4 shared

Labs

• Laurence U Buxbaum LabPI