James A. MacLean, M.D.

Specialty: Allergy

North Shore Medical Center

114 R Highland Avenue
Salem, MA 01970


The following is a list of recent publications for which this Partners Asthma Center physician has been cited as an author in PubMed databases. Study abstracts have been provided for your convenience.

MacLean, J. A. and P. J. Hannaway (2003). "Angioedema and AT1 receptor blockers: proceed with caution." Arch Intern Med 163(12): 1488-9; author reply 1489.

MacLean, J. A., 2nd, A. Chakrabarty, et al. (2003). "Family of Kunitz proteins from trophoblast: Expression of the trophoblast Kunitz domain proteins (TKDP) in cattle and sheep." Mol Reprod Dev 65(1): 30-40.

Here we report the molecular cloning of several members of a family of novel proteins expressed by the ruminant trophoblast, known as the trophoblast Kunitz domain proteins (TKDPs). Each contains a carboxyl-terminal module of approximately 64 amino acids belonging to the Kunitz family of serine proteinase inhibitors. These Kunitz modules are preceded by one or more structurally related domains, each about 80 amino acids long. The function of these domains is unclear. The TKDPs differ considerably in sequence identity, with much of the diversity due to variability in the amino-terminal domains. However, nine of the ten Kunitz domains described here are themselves unique, ranging in amino acid sequence identity from 90% to 53% to each other and averaging only about 50% identity with bovine pancreatic trypsin inhibitor (BPTI). The "warhead" P1 residues, which govern specificity, are themselves variable and include some unusual amino acids, such as Asn, Thr, and Ile, as well as the more common Lys. The Kunitz domains of three of the TKDPs lack the conserved cysteines at positions 14 and 38 (BPTI numbering) that normally contribute to the orientation of the inhibitory loop. Northern blotting and reverse transcription-polymerase chain reaction (RT-PCR) demonstrated that the TKDP genes do not exhibit identical expression patterns during trophoblast development, although mostly are expressed maximally during early pregnancy. It is possible that the TKDPs provide a broad range of specificities against maternal proteinases that might be damaging to the trophoblast during pregnancy. Mol. Reprod. Dev. 65: 30-40, 2003.

Wayne, C. M., J. A. MacLean, et al. (2002). "Two novel human X-linked homeobox genes, hPEPP1 and hPEPP2, selectively expressed in the testis." Gene 301(1-2): 1-11.

The PEPP genes are a recently described subfamily of mouse homeobox genes preferentially expressed in reproductive tissues. Pem, the founding member of the PEPP subfamily, has undergone rapid divergence due to positive selection, rendering the identification of its human orthologue difficult. Here we report the isolation and characterization of two human homeobox genes, hPEPP1 and hPEPP2, that are related to Pem and other PEPP family members. We identified these human genes based on their location in Xq24, which is syntenic to the mouse X-chromosome region containing three PEPP genes: Pem, Psx-1, and Psx-2. We found that hPEPP1 and hPEPP2 are selectively expressed in the testis, where the mouse and rat Pem genes are also expressed. However, unlike all mouse PEPP genes, hPEPP1 and hPEPP2 were not expressed in placenta, which suggests the possibility that the regulation of PEPP genes has significantly changed since the split between hominids and rodents. Although hPEPP1 exhibits highly selective expression in normal tissues, it is aberrantly expressed in tumor cell lines from several different organs, analogous to the expression pattern of mouse and rat Pem but not mouse Psx-1 or Psx-2. We conclude that we identified two human homeobox genes from the PEPP subfamily that are good candidates to encode transcription factors that regulate downstream genes and biological events in the human testis.

Medoff, B. D., A. Sauty, et al. (2002). "IFN-gamma-inducible protein 10 (CXCL10) contributes to airway hyperreactivity and airway inflammation in a mouse model of asthma." J Immunol 168(10): 5278-86.

Allergic asthma is an inflammatory disease of the airways characterized by eosinophilic inflammation and airway hyper-reactivity. Cytokines and chemokines specific for Th2-type inflammation predominate in asthma and in animal models of this disease. The role of Th1-type inflammatory mediators in asthma remains controversial. IFN-gamma-inducible protein 10 (IP-10; CXCL10) is an IFN-gamma-inducible chemokine that preferentially attracts activated Th1 lymphocytes. IP-10 is up-regulated in the airways of asthmatics, but its function in asthma is unclear. To investigate the role of IP-10 in allergic airway disease, we examined the expression of IP-10 in a murine model of asthma and the effects of overexpression and deletion of IP-10 in this model using IP-10-transgenic and IP-10-deficient mice. Our experiments demonstrate that IP-10 is up-regulated in the lung after allergen challenge. Mice that overexpress IP-10 in the lung exhibited significantly increased airway hyperreactivity, eosinophilia, IL-4 levels, and CD8(+) lymphocyte recruitment compared with wild-type controls. In addition, there was an increase in the percentage of IL-4-secreting T lymphocytes in the lungs of IP-10-transgenic mice. In contrast, mice deficient in IP-10 demonstrated the opposite results compared with wild-type controls, with a significant reduction in these measures of Th2-type allergic airway inflammation. Our results demonstrate that IP-10, a Th1-type chemokine, is up-regulated in allergic pulmonary inflammation and that this contributes to the airway hyperreactivity and Th2-type inflammation seen in this model of asthma.

Silverman, E. S., G. T. De Sanctis, et al. (2001). "The transcription factor early growth-response factor 1 modulates tumor necrosis factor-alpha, immunoglobulin E, and airway responsiveness in mice." Am J Respir Crit Care Med 163(3 Pt 1): 778-85.

Early growth-response factor 1 (Egr-1) is a sequence-specific transcription factor that plays a regulatory role in the expression of many genes important in inflammation, cell growth, apoptosis, and the pathogenesis of disease. In vitro studies suggest that Egr-1 is capable of regulating the expression of tumor necrosis factor-alpha (TNF-alpha) and other genes involved in airway inflammation and reactivity following allergen stimulation. On the basis of these data, we hypothesized that in the absence of Egr-1, the TNF-alpha response and subsequent downstream inflammatory events that usually follow allergen challenge would be diminished. To test our hypothesis Egr-1 knock-out (KO) mice were examined in an ovalbumin (OVA)-induced model of airway inflammation and reactivity, and compared with identically treated wild-type (WT) control mice. In response to OVA sensitization and airway challenge, KO mice had diminished TNF-alpha mRNA and protein in the lungs and mast cells compared with WT mice. Interestingly, the KO mice had elevated IgE levels at baseline and after allergen challenge compared with WT mice. Furthermore, the airways of KO mice were hyporesponsive to methacholine challenge at baseline and after allergen challenge. These data indicate that Egr-1 modulates TNF-alpha, IgE, and airway responsiveness in mice.

Mathew, A., J. A. MacLean, et al. (2001). "Signal transducer and activator of transcription 6 controls chemokine production and T helper cell type 2 cell trafficking in allergic pulmonary inflammation." J Exp Med 193(9): 1087-96.

Antigen-specific CD4 T helper type 2 (Th2) cells play a pivotal role in the induction of allergic asthma, but the mechanisms regulating their recruitment into the airways are unknown. Signal transducer and activator of transcription factor (Stat)6 is a transcription factor essential for Th2 cell differentiation. Here we show that Stat6 also controls Th2 cell recruitment and effector function in allergic inflammation in vivo. To isolate the role of Stat6 in regulating Th2 cell trafficking and effector function from its role in Th2 cell differentiation, we used a murine model of asthma in which in vitro-differentiated Stat6(+/+) antigen-specific Th2 cells were adoptively transferred into naive Stat6(-/-) and Stat6(+/+) mice followed by aerosol antigen challenge. We found that all of the features of asthma, including Th2 cell accumulation, Th2 and eosinophil-active chemokine production, and airway eosinophilia, mucus production, and hyperresponsiveness seen in Stat6(+/+) mice, were dramatically absent in Stat6(-/)- mice that received Stat6(+/)+ antigen-specific Th2 cells. Our findings establish Stat6 as essential for Th2 cell trafficking and effector function and suggest that interruption of Stat6 signaling in resident cells of the lung is a novel approach to asthma therapy.

MacLean, J. A. and F. J. Eidelman (2001). "The genetics of atopy and atopic eczema." Arch Dermatol 137(11): 1474-6.

Wong, J. T., C. S. Nagy, et al. (2000). "Rapid oral challenge-desensitization for patients with aspirin-related urticaria-angioedema." J Allergy Clin Immunol 105(5): 997-1001.

BACKGROUND: Acetylsalicylic acid (ASA), commonly known as aspirin, is indicated in the treatment of coronary artery disease (CAD). Many patients are denied treatment with ASA because of a history of ASA or nonsteroidal anti-inflammatory drug (NSAID)-induced urticaria or angioedema. OBJECTIVE: We sought to develop a safe and practical protocol to allow the administration of ASA to patients with a history of ASA- or NSAID-induced urticaria-angioedema. METHODS: Eleven subjects with a history of ASA- or NSAID-induced urticaria-angioedema were challenged-desensitized by oral protocols based on rapidly escalating doses of ASA. Most had CAD, one had a history of pulmonary embolism, and one had refractory chronic sinusitis and asthma. Starting doses ranged from 0.1 to 10 mg and were administered at intervals of 10 to 30 minutes. Dosing was individualized for each patient but followed this general sequence (in milligrams): 0.1, 0.3, 1, 3, 10, 20, 40, 81, 162, 325. RESULTS: Nine patients tolerated the procedure without adverse effects and continued taking ASA for periods ranging from 1 to 24 months, without development of urticaria or angioedema. A patient who had a history of chronic idiopathic urticaria in addition to aspirin-induced urticaria had chest tightness during the protocol. Another patient who had continuing urticaria and angioedema associated with antithyroid antibodies developed angioedema several hours after completing the protocol. CONCLUSION: In patients with historical ASA- or NSAID-induced urticaria-angioedema reactions but who did not have urticaria and angioedema independent of ASA/NSAID, rapid oral challenge-desensitization to ASA was performed safely and permitted patients with CAD and other diseases to receive treatment with ASA.

MacLean, J. A., G. T. De Sanctis, et al. (2000). "CC chemokine receptor-2 is not essential for the development of antigen-induced pulmonary eosinophilia and airway hyperresponsiveness." J Immunol 165(11): 6568-75.

Monocyte chemoattractant proteins-1 and -5 have been implicated as important mediators of allergic pulmonary inflammation in murine models of asthma. The only identified receptor for these two chemokines to date is the CCR2. To study the role of CCR2 in a murine model of Ag-induced asthma, we compared the pathologic and physiological responses of CCR2(-/-) mice with those of wild-type (WT) littermates following immunization and challenge with OVA. OVA-immunized/OVA-challenged (OVA/OVA) WT and CCR2(-/-) mice developed significant increases in total cells recovered by bronchoalveolar lavage (BAL) compared with their respective OVA-immunized/PBS-challenged (OVA/PBS) control groups. There were no significant differences in BAL cell counts and differentials (i.e., macrophages, PMNs, lymphocytes, and eosinophils) between OVA/OVA WT and CCR2(-/-) mice. Serologic evaluation revealed no significant difference in total IgE and OVA-specific IgE between OVA/OVA WT mice and CCR2(-/-) mice. Lung mRNA expression and BAL cytokine protein levels of IL-4, IL-5, and IFN-gamma were also similar in WT and CCR2(-/-) mice. Finally, OVA/OVA CCR2(-/-) mice developed increased airway hyper-responsiveness to a degree similar to that in WT mice. We conclude that following repeated airway challenges with Ag in sensitized mice, the development of Th2 responses (elevated IgE, pulmonary eosinophilia, and lung cytokine levels of IL-4 and IL5) and the development of airway hyper-responsiveness are not diminished by a deficiency in CCR2.

Khan, I. A., J. A. MacLean, et al. (2000). "IP-10 is critical for effector T cell trafficking and host survival in Toxoplasma gondii infection." Immunity 12(5): 483-94.

The generation of an adaptive immune response against intracellular pathogens requires the recruitment of effector T cells to sites of infection. Here we show that the chemokine IP-10, a specific chemoattractant for activated T cells, controls this process in mice naturally infected with Toxoplasma gondii. Neutralization of IP-10 in infected mice inhibited the massive influx of T cells into tissues and impaired antigen-specific T cell effector functions. This resulted in >1000-fold increase in tissue parasite burden and a marked increase in mortality compared to control antibody-treated mice. These observations suggest that IP-10 may play a broader role in the localization and function of effector T cells at sites of Th1 inflammation.

Chen, H. J., K. J. Bloch, et al. (2000). "Acute eosinophilic hepatitis from trovafloxacin." N Engl J Med 342(5): 359-60.

MacLean, J. A., A. Sauty, et al. (1999). "Antigen-induced airway hyperresponsiveness, pulmonary eosinophilia, and chemokine expression in B cell-deficient mice." Am J Respir Cell Mol Biol 20(3): 379-87.

Murine models of allergen-induced pulmonary inflammation share many features with human asthma, including the development of antigen-induced pulmonary eosinophilia, airway hyperresponsiveness, antigen-specific cellular and antibody responses, the elaboration of Th2 cytokines (interleukin [IL]-4 and IL-5), and the expression of chemokines with activity for eosinophils. We examined the role of B cells and antigen-specific antibody responses in such a model by studying the histopathologic and physiologic responses of B cell-deficient mice compared with wild-type controls, following systemic immunization and airway challenge with ovalbumin (OVA). Both OVA-challenged wild-type and B cell-deficient mice developed (1) airway hyperresponsiveness, (2) pulmonary inflammation with activated T cells and eosinophils, (3) IL-4 and IL-5 secretion into the airway lumen, and (4) increased expression of the eosinophil active chemokines eotaxin and monocyte chemotactic protein-3. There were no significant differences in either the pathologic or physiologic responses in the B cell-deficient mice compared with wild-type mice. These data indicate that B cells and antigen-specific antibodies are not required for the development of airway hyperresponsiveness, eosinophilic pulmonary inflammation, and chemokine expression in sensitized mice following aerosol challenge with antigen.

De Sanctis, G. T., J. A. MacLean, et al. (1999). "Contribution of nitric oxide synthases 1, 2, and 3 to airway hyperresponsiveness and inflammation in a murine model of asthma." J Exp Med 189(10): 1621-30.

Asthma is a chronic disease characterized by increased airway responsiveness and airway inflammation. The functional role of nitric oxide (NO) and the various nitric oxide synthase (NOS) isoforms in human asthma is controversial. To investigate the role of NO in an established model of allergic asthma, mice with targeted deletions of the three known isoforms of NOS (NOS1, 2, and 3) were studied. Although the inducible (NOS2) isoform was significantly upregulated in the lungs of ovalbumin (OVA)-sensitized and -challenged (OVA/OVA) wild-type (WT) mice and was undetectable in similarly treated NOS2-deficient mice, airway responsiveness was not significantly different between these groups. OVA/OVA endothelial (NOS3)-deficient mice were significantly more responsive to methacholine challenge compared with similarly treated NOS1 and NOS1&3-deficient mice. Airway responsiveness in OVA/OVA neuronal (NOS1)-deficient and neuronal/endothelial (NOS1&3) double-deficient mice was significantly less than that observed in similarly treated NOS2 and WT groups. These findings demonstrate an important function for the nNOS isoform in controlling the inducibility of airway hyperresponsiveness in this model of allergic asthma.

De Sanctis, G. T., J. A. MacLean, et al. (1999). "Interleukin-8 receptor modulates IgE production and B-cell expansion and trafficking in allergen-induced pulmonary inflammation." J Clin Invest 103(4): 507-15.

We examined the role of the interleukin-8 (IL-8) receptor in a murine model of allergen-induced pulmonary inflammation using mice with a targeted deletion of the murine IL-8 receptor homologue (IL-8r-/-). Wild-type (Wt) and IL-8r-/- mice were systemically immunized to ovalbumin (OVA) and were exposed with either single or multiple challenge of aerosolized phosphate-buffered saline (OVA/PBS) or OVA (OVA/OVA). Analysis of cells recovered from bronchoalveolar lavage (BAL) revealed a diminished recruitment of neutrophils to the airway lumen after single challenge in IL-8r-/- mice compared with Wt mice, whereas multiply challenged IL-8r-/- mice had increased B cells and fewer neutrophils compared with Wt mice. Both Wt and IL-8r-/- OVA/OVA mice recruited similar numbers of eosinophils to the BAL fluid and exhibited comparable degrees of pulmonary inflammation histologically. Both total and OVA-specific IgE levels were greater in multiply challenged IL-8r-/- OVA/OVA mice than in Wt mice. Both the IL-8r-/- OVA/OVA and OVA/PBS mice were significantly less responsive to methacholine than their respective Wt groups, but both Wt and IL-8r mice showed similar degrees of enhancement after multiple allergen challenge. The data demonstrate that the IL-8r modulates IgE production, airway responsiveness, and the composition of the cells (B cells and neutrophils) recruited to the airway lumen in response to antigen.

Luster, A. D., R. D. Cardiff, et al. (1998). "Delayed wound healing and disorganized neovascularization in transgenic mice expressing the IP-10 chemokine." Proc Assoc Am Physicians 110(3): 183-96.

IP-10 is a member of the alpha or cysteine-X amino acid-cysteine (CXC) chemokine family of chemotactic cytokines. High levels of IP-10 expression have been detected in a number of chronic human inflammatory conditions, including psoriasis, a common inflammatory disease of the skin. IP-10 has been shown to chemoattract activated T cells, inhibit the proliferation of endothelial cells, and inhibit the growth of tumors in vivo. To determine the capacity of IP-10 to modulate the inflammatory response in vivo, we have created transgenic mice that constitutively express IP-10 from keratinocytes. These mice developed normally and, in general, did not spontaneously recruit leukocytes into the skin or other organs that expressed the transgene. In addition, the transgenic mice had a normal cutaneous contact hypersensitivity cellular immune response. However, IP-10 transgenic mice had an abnormal wound healing response characterized by a more intense inflammatory phase and a prolonged and disorganized granulation phase with impaired blood vessel formation. These results have demonstrated that IP-10 can inhibit the neovascularization associated with a physiological response in vivo and have revealed a novel biologic activity of IP-10 as an inhibitor of wound healing.

Sarafi, M. N., E. A. Garcia-Zepeda, et al. (1997). "Murine monocyte chemoattractant protein (MCP)-5: a novel CC chemokine that is a structural and functional homologue of human MCP-1." J Exp Med 185(1): 99-109.

The chemokines are a large family of cytokines that control the recruitment of leukocytes in immune and inflammatory responses. We describe the isolation of a novel murine CC chemokine that, based on its biological and structural features, we have named monocyte chemoattractant protein (MCP)-5. MCP-5 mapped to the CC chemokine cluster on mouse chromosome 11 and was most closely related to human MCP-1 in structure (66% amino acid identity). Purified recombinant MCP-5 protein was a potent chemoattractant for peripheral blood monocytes, was only weakly active on eosinophils at high doses, and was inactive on neutrophils. MCP-5 induced a calcium flux in peripheral blood mononuclear cells, but not in purified murine eosinophils or neutrophils. Consistent with these results, MCP-5 induced a calcium flux in human embryonic kidney (HEK)-293 cells transfected with human and murine CCR2, a CC chemokine receptor expressed on monocytes. MCP-5 did not induce a calcium flux in HEK-293 cells transfected with CCR1, CCR3, or CCR5. Constitutive expression of MCP-5 mRNA was detected predominantly in lymph nodes, and its expression was markedly induced in macrophages activated in vitro and in vivo. Moreover, MCP-5 expression was up-regulated in the lungs of mice following aerosolized antigen challenge of sensitized mice, and during the host response to infection with Nippostrongylus brasiliensis. These data indicate that MCP-5 is a novel and potent monocyte active chemokine that is involved in allergic inflammation and the host response to pathogens.

Rothenberg, M. E., J. A. MacLean, et al. (1997). "Targeted disruption of the chemokine eotaxin partially reduces antigen-induced tissue eosinophilia." J Exp Med 185(4): 785-90.

The chemokines are a large group of chemotactic cytokines that regulate leukocyte trafficking and have recently been shown to inhibit human immunodeficiency virus entry into cells. Eotaxin is a C-C chemokine implicated in the recruitment of eosinophils in a variety of inflammatory disorders and, unlike all other eosinophil chemoattractants, is eosinophil specific. However, given the large number of chemoattractants that have activities on eosinophils, it is unclear whether eotaxin has an important role in vivo. Furthermore, it remains unclear why there is constitutive expression of eotaxin in healthy states in the absence of eosinophilic inflammation. To begin to determine the significance of eotaxin at baseline and during eosinophil-mediated disease processes, we have used targeted gene disruption to generate mice that are deficient in eotaxin. Such mice demonstrate that eotaxin enhances the magnitude of the early (but not late) eosinophil recruitment after antigen challenge in models of asthma and stromal keratitis. Surprisingly, a role for eotaxin in regulating the constitutive number of eosinophils in the peripheral circulation is also demonstrated. These results indicate a contributory role for eotaxin in the generation of peripheral blood and antigen-induced tissue eosinophilia.

Sharma, S. K., J. A. MacLean, et al. (1996). "The effect of an anti-CD3 monoclonal antibody on bleomycin-induced lymphokine production and lung injury." Am J Respir Crit Care Med 154(1): 193-200.

Acute lung injury was produced in C57BL/6 mice by the intratracheal (i.t.) administration of bleomycin (BLM). Following injection of 0.1 U BLM, CD3+ lymphocytes and the production of the T-helper-1 (Th1) lymphokines interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) were increased in lung and lymph nodes. The production of the Th2 cytokine IL-4 by lung lymphocytes was decreased. Intraperitoneal (i.p.) injection of a rat antimurine CD3 (YCD3) monoclonal antibody (mAb) blocked the accumulation of pulmonary CD3+ cells for up to 14 d and effectively suppressed IL-2 and IL-4 but not IFN-gamma production by lung lymphocytes throughout the protocol. Secretion of all of the above lymphokines by lymph node cells was inhibited by YCD3 treatment. Administration of YCD3 diminished pulmonary fibrosis and increased survival (p < 0.01) following BLM administration compared with mice treated with an isotype-matched control mAb. Initiating treatment with YCD3 at Days 5-7 following BLM also decreased pulmonary fibrosis and significantly reduced mortality (p < 0.02). We conclude that BLM yields a potentially lethal fibroinflammatory response in the lung that is markedly diminished by antagonizing the functional activities of CD3+ cells in vivo.

MacLean, J. A., R. Ownbey, et al. (1996). "T cell-dependent regulation of eotaxin in antigen-induced pulmonary eosinophila." J Exp Med 184(4): 1461-9.

T lymphocytes have been implicated in controlling the recruitment of eosinophils into the lung in murine models of allergic asthma. The mechanism by which T cells assist in the recruitment of eosinophils to the lung in these models is not completely understood. We hypothesized that eosinophil-active chemokines might be regulated by antigen (Ag)-induced T cell activation in vivo and thereby mediate T cell-dependent eosinophil recruitment. To test this hypothesis, we examined the effect of an anti-CD3 mAb on Ag-induced pulmonary eosinophilia and correlated this with the expression of three eosinophil-active chemokines: eotaxin, macrophage inflammatory protein (MIP)-1 alpha, and RANTES. We found that Ag-induced pulmonary eosinophilia was associated with the induction of eotaxin and MIP-1 alpha, but not RANTES mRNA. Prechallenge treatment with anti-CD3 mAb inhibited eotaxin, but not MIP-1 alpha and RANTES mRNA induction, and significantly reduced eosinophil accumulation in the lung. In addition, Ag-specific antibody responses and mast cell degranulation after Ag challenge in sensitized mice were not affected by T cell elimination, and were not sufficient to induce the expression of eotaxin and cause pulmonary eosinophilia. These findings suggest that eotaxin is one of the molecular links between Ag-specific T cell activation and the recruitment of eosinophils into the airways.

MacLean, J. A., W. Xia, et al. (1996). "Sequestration of inhaled particulate antigens by lung phagocytes. A mechanism for the effective inhibition of pulmonary cell-mediated immunity." Am J Pathol 148(2): 657-66.

Dendritic cells (DCs) have emerged as the dominant antigen-presenting cells (APCs) of the lung, playing a vital role in the induction of cell-mediated immunity to inhaled antigens. We have previously demonstrated that an airway challenge with the soluble antigen hen egg lysozyme yields rapid acquisition of specific antigen-presenting cell activity by purified pulmonary DCs and a cell-mediated immune response in the lung upon secondary challenge. To examine how a particulate antigen leads to a cell-mediated response in vivo, graded concentrations of heat-killed Listeria (HKL) were injected intratracheally into Lewis rats. The bacteria were rapidly ingested by lung macrophages and polymorphonuclear leukocytes. The ability of purified pulmonary DCs pulsed in vivo by an airway challenge with HKL to subsequently stimulate HKL-specific responses ex vivo showed a threshold response, requiring a dose in excess of 10(9) organisms/rat. By contrast, all dosages of HKL yielded specific sensitization of lymphocytes in the draining bilar nodes. Pulmonary DCs purified from rats after a secondary in vivo airway challenge with HKL at day 14 were ineffective antigen-presenting cells except at high dosages of antigen. The generation of cell-mediated pulmonary inflammation paralleled the antigen-presenting cell activity of pulmonary DCs and was observed only at high antigen dosages. Hen egg lysozyme immobilized onto polystyrene beads and injected intratracheally yielded comparable results to those observed with HKL. We suggest that a pulmonary cellular immune response is generated to an inhaled particulate antigen when the protective phagocytic capacities of the lung are exceeded and antigen is able to interact directly with interstitial DCs. The diversion of particulate antigens by pulmonary phagocytes may help to limit undesirable pulmonary inflammation while allowing the generation of antigen-specific immune lymphocytes in vivo.

MacLean, J. A., Z. Su, et al. (1995). "Anti-CD3:anti-IL-2 receptor-bispecific mAb-mediated immunomodulation. Low systemic toxicity, differential effect on lymphoid tissue, and inhibition of cell-mediated hypersensitivity." J Immunol 155(7): 3674-82.

An anti-CD3:anti-CD25 (CD3,25) bispecific mAb was developed with the objective of combining the advantages of the parent anti-CD3 and anti-CD25 mAbs. The in vivo effects of the CD3,25 were examined in comparison to the parent Abs. The CD3,25 was well tolerated in vivo, in contrast to the parent anti-CD3 mAb, which induced systemic toxicity in recipient animals. Anti-CD3 mAb induced cell death, lymphoblast formation, and T cell activation in peripheral lymphoid organs; these were observed to a lesser extent in CD3,25-treated animals. In the thymus, anti-CD3 caused a progressive depletion of the CD4+ CD8+ "double positive" thymocytes, which was not seen in CD3,25-treated animals. This finding suggests that monovalent CD3 binding is insufficient to induce thymocyte apoptosis. Animals treated with a combination of anti-CD3 and anti-CD25 mAbs demonstrated changes in the lymphoid organs that were similar to anti-CD3-treated mice. This finding demonstrates that the effect of the CD3,25 is different than the sum of the parent Abs and suggests that the bispecific nature of the CD3,25 results in a reagent with unique immunomodulatory properties. The functional efficacy of the CD3,25 was assessed in a murine model of delayed-type hypersensitivity. The CD3,25 was as effective as the anti-CD3 mAb in inhibiting the delayed-type hypersensitivity reaction and was more effective than the parent anti-CD25 mAb. These data demonstrate that appropriately designed bispecific mAbs can be used as effective immunosuppressive agents with low systemic toxicity.

Wong, J. T., R. E. Ripple, et al. (1994). "Vancomycin hypersensitivity: synergism with narcotics and "desensitization" by a rapid continuous intravenous protocol." J Allergy Clin Immunol 94(2 Pt 1): 189-94.

BACKGROUND: We examined the clinical spectrum of patients with persistent adverse reactions to vancomycin, assessed contributing factors, and evaluated the efficacy and safety of a rapid continuous intravenous "desensitization" protocol in these patients. METHODS: Seven patients with serious staphylococcal infections resistant to beta-lactam antibiotics whose adverse reactions to vancomycin persisted despite slowing of the vancomycin infusion and pretreatment with H1-antihistamine were studied. All seven patients underwent a rapid continuous intravenous desensitization protocol with multiple small increases in vancomycin concentration tightly regulated with a syringe pump. RESULTS: Most of the seven patients safely achieved, during the first day, a vancomycin infusion rate (VIR) sufficient, or close to sufficient, to provide the desired vancomycin dose. In three patients there appeared to be a threshold VIR beyond which adverse reactions were repeatedly elicited; these reactions abated when the VIR was slightly lowered. Narcotic administration was found to adversely affect treatment with vancomycin. After concurrent narcotic administration was discontinued in three patients, they and the other four patients successfully completed the full course of treatment with vancomycin. CONCLUSION: Patients whose adverse reactions to vancomycin did not respond to slowing of the infusion rate and additional H1-antihistamines can be safely treated with a rapid continuous intravenous desensitization protocol and discontinuance of narcotic administration.

MacLean, J. A., Z. Su, et al. (1993). "Anti-CD3:anti-IL-2 receptor bispecific monoclonal antibody. Targeting of activated T cells in vitro." J Immunol 150(4): 1619-28.

T cells are major mediators of graft rejection and many autoimmune diseases. During the Ag recognition process, T cells often become activated. We tested the hypothesis that an anti-CD3:anti-CD25 (CD3,25) bispecific mAb (BSMAB) can effectively and selectively target activated T cells. By flow cytometric analysis, the CD3,25 BSMAB was shown to bind avidly to activated T cells that coexpress CD3 and CD25 (p55 chain of the IL-2R), achieving higher levels than the parent anti-CD3 and anti-CD25 mAb. It bound only weakly to unstimulated T cells. The CD3,25 BSMAB effectively redirected CTL to lyse CD25-bearing PHA-stimulated T lymphoblasts and the IL2-dependent CTLL tumor cell line in chromium release assays. It was highly effective in blocking MLR as shown by inhibition of [3H]TdR incorporation. However, the CD3,25 BSMAB has a low potential to activate resting T cells, as it induced only minimal [3H]TdR incorporation even in the presence of exogenous IL-2. In the absence of exogenous IL-2, the CD3,25 BSMAB was unable to induce [3H]TdR incorporation. In contrast, the parent anti-CD3 mAb induced a high degree of incorporation. In summary, the CD3,25 BSMAB selectively targets activated CD25-expressing T cells and lymphomas although maintaining a low activation potential for unstimulated T cells, potentially advantageous properties that can be exploited for immunotherapy.

MacLean, J. A., R. Moscicki, et al. (1990). "Adverse reactions to heparin." Ann Allergy 65(4): 254-9.

Heparin is a medication that has gained widespread use in clinical medicine as the therapy of choice for acute anticoagulation in the prevention and treatment of thromboembolic disease. Therapy with heparin is associated with many potential adverse side effects. Heparin-induced skin necrosis is an uncommon complication of heparin therapy that is now believed to be a thrombotic complication of heparin-induced thrombocytopenia. The pathogenesis of this disorder is unknown, but it is presumed to be immunologically mediated. The diagnosis is frequently one of exclusion. Significant morbidity and mortality may arise from failure to recognize this adverse reaction.

MacLean, J. A., D. H. Eidelman, et al. (1989). "Bilateral cavitary lung disease in a 29-year-old woman." Chest 96(3): 657-8.

Small, M., H. N. Cohen, et al. (1986). "Impaired thyrotrophin secretion following the administration of thyrotrophin-releasing hormone in type II diabetes mellitus." Postgrad Med J 62(728): 445-8.

Serum thyrotrophin has been measured before and after the intravenous administration of 200 micrograms of thyrotrophin-releasing hormone in 91 white subjects (33 stable diabetic patients and 58 healthy controls), none of whom had any clinical evidence of thyroid or pituitary dysfunction. Seven of the diabetic subjects failed to achieve a rise of serum thyrotrophin of greater than 2 mU/l above basal concentrations, as compared with only one of the control subjects (P = 0.006). The difference in response between diabetics and controls was confined to patients with Type II (non-insulin-dependent) diabetes: thus 5 of 13 Type II patients and 2 of 20 Type I (insulin-dependent) patients failed to show a normal response to thyrotrophin releasing hormone injection. No significant effect of glycaemic control on thyrotrophin responses was noted. These results suggest that Type II diabetes mellitus may be a cause of impaired thyrotrophin secretion in patients with no clinical evidence of pituitary disease. The mechanism for this impaired pituitary hormone release remains to be clarified.

Small, M., J. A. MacLean, et al. (1984). "Haemostatic effects of stanozolol in elderly medical patients." Thromb Res 35(3): 353-8.

Small, M., H. N. Cohen, et al. (1984). "Serum growth hormone (GH) and the responses to thyrotropin-releasing hormone (TRH) in diabetes mellitus: lack of evidence for TRH evoked GH secretion." Diabetes Res 1(2): 89-94.

Since TRH has been reported to evoke GH secretion in diabetic patients, we have investigated the influences of the enhanced GH secretion normally seen in diabetic patients on this response by measuring serum GH concentrations in 27 non-ketotic, stable, insulin-dependent diabetic (IDD) patients (14 male, 13 female). GH concentrations were measured over periods of 1 hr prior to and 1 hr following IV administration of both 200 micrograms TRH and 2 ml N Saline given on separate days. GH concentrations were not statistically significantly different between males and females during the two 120 min test periods and in individual patients GH concentrations did not differ significantly at any time during the tests. Sixteen of the 27 patients (Group 1) demonstrated elevation of serum GH following TRH, which was not statistically different from 11 of 27 patients who showed increased GH concentrations following saline administration. Seven subjects (4 male, 3 female) had a higher peak GH concentration following TRH than during their own 2 pre-injection test periods or following saline. Eleven patients failed to show any GH rise following IV TRH (Group 2). During the TRH test periods integrated GH concentrations in Group 1 patients were not statistically significantly different from those of Group 2: Group 1, 7.1 (0.7-15.8) (median and range) mU.min.l(-1), Group 2, 2.7 (0.4-25.4) mU.min.l(-1).(ABSTRACT TRUNCATED AT 250 WORDS)