[Radiation-induced lymphopenia: Lymphocytes as a new organ at risk]. / Lymphopénie radio-induite : les lymphocytes comme nouvel organe à risque.

Taking the immune system into account in the fight against tumors has upset the cancer treatment paradigm in the 21st century. Combination treatment strategies associating radiotherapy with immunotherapy are being increasingly implemented in clinical practice. In this context, lymphocytes, whether lymphocytes infiltrating the tumour, circulating blood lymphocytes or lymphocytes residing within the lymph nodes, are key players in cellular and humoral anti-tumor immunity. The significant radiosensitivity of lymphocytes was demonstrated in the early 1990s. Along with the cells of the digestive mucosa, lymphocytes are thus among the most radiosensitive cell types in the body. Compared to the old practices of external radiotherapy, current intensity modulated treatments have allowed a considerable improvement in acute and late toxicity, at the cost of a significant increase in the volume irradiated at low doses. This is not without consequence on the incidence of radiation-induced lymphopenia, with prognostic implications for many tumor types. Thus, in order not to hinder the action of antitumor immunity and the efficacy of immunotherapy, it is essential to consider lymphocytes as a new organ at risk in its own right. In this development, based on current data from the literature, we will begin by justifying the necessary prevention of radiation-induced lymphopenia, before providing the tools currently known to apprehend lymphocytes as a new multicompartments. Finally, we will broaden the perspective by outlining ways to develop research in this area.

Lymphocyte sparing normal tissue effects in the clinic (LymphoTEC): A systematic review of dose constraint considerations to mitigate radiation-related lymphopenia in the era of immunotherapy.

BACKGROUND: Radiation-related lymphopenia has been associated with suboptimal tumor control rates leading to inferior survival outcomes. To date, no standardized dose constraints are available to limit radiation dose to resident and circulating lymphocyte populations. We undertook this systemic review of the literature to provide a synopsis of the dosimetric predictors of radiation-related lymphopenia in solid malignancies. METHODOLOGY: A systematic literature review of PubMed (National Institutes of Health), Cochrane Central (Cochrane collaboration), and Google Scholar was conducted with the following keywords: "radiation", "lymphopenia", "cancer", "dosimetric predictors" with an inclusion deadline of May 31, 2022. Studies that met prespecified inclusion criteria were designated either Good, Fair, or Poor Quality based on the Newcastle-Ottawa quality assessment. The dosimetric parameters derived from Good Quality studies were tabulated as LymphoTEC dose constraints. Dosimetric parameters derived from Fair and Poor-quality studies were grouped as optional. RESULTS: An initial systematic search of the literature yielded 1,632 articles. After screening, a total of 48 studies met inclusion criteria and were divided into the following categories: central nervous system (CNS, 6), thoracic (11), gastrointestinal (26), gynecologic (2), head and neck, breast, and genitourinary (one each) cancers. Lung mean dose, heart mean dose, brain V25, spleen mean dose, estimated dose to immune cells, and bone marrow V10 were among the strongest predictors for severe lymphopenia related to radiotherapy. CONCLUSION: Optimizing the delivery of radiation therapy to limit dose to lymphocyte-rich structures may curb the negative oncologic impact of lymphocyte depletion. The dose constraints described herein may be considered for prospective validation and future use in clinical trials to limit risk of radiation-related lymphopenia and possibly improve cancer-associated outcomes.

Role of Interleukin-7 in the Development of and Recovery from Radiation-Induced Lymphopenia: A Post-hoc Analysis of a Prospective Cohort.

PURPOSE: Radiation-induced lymphopenia is associated with worse outcomes in solid tumors. We assessed the impact of interleukin-7 (IL-7), a key cytokine in lymphocyte homeostasis, on radiation-induced lymphopenia. MATERIALS AND METHODS: A post-hoc analysis was performed in a prospective cohort of 98 patients with hepatocellular carcinoma who were treated with radiotherapy in 2016-2018. Blood IL-7 levels were assayed before and at the end of radiotherapy. Acute severe lymphopenia (ASL) was defined as a total lymphocyte count of < 200/µL during radiotherapy. Cox and logistic regression analyses were performed to identify predictors of survival and ASL development, respectively. RESULTS: Patients with ASL (n=41) had significantly poorer overall survival than those without (12.0 months vs. 25.3 months, p=0.001). Patients with lymphocyte recovery showed significantly longer overall survival than those without (21.8 months vs. 10.3 months, p=0.042). ASL was an independent predictor of poor survival (hazard ratio, 2.07; p=0.015). Patients with ASL had significantly lower pre-radiotherapy IL-7 levels (2.07 pg/mL vs. 3.01 pg/mL, p=0.010). A high pre-radiotherapy IL-7 level was an independent predictor of a reduced risk of ASL development (hazard ratio, 0.40; p=0.004). IL-7 levels reflected a feedback response to ASL, with a higher ΔIL-7 in patients with ASL and a lower ΔIL-7 in those without ASL (0.48 pg/mL vs. -0.66 pg/mL, p < 0.001). Post-radiotherapy IL-7 levels were significantly positively correlated with the total lymphocyte counts at 2 months. CONCLUSION: IL-7 is associated with the development of and recovery from ASL, which may impact survival. To overcome radiation-induced lymphopenia, a novel strategy using IL-7 may be considered.

Early use of non-steroidal anti-inflammatory drugs in COVID-19 might reverse pathogenesis, prevent complications and improve clinical outcomes.

The pathogenesis of Coronavirus disease 2019 is still obscure and the need for exploration of possible mechanisms to suggest drugs based on knowledge should never be delayed. In this manuscript, we present a novel theory to explain the pathogenesis of COVID-19; lymphocyte distraction theory upon which the author has used, in a preprinted protocol, non-steroidal anti-inflammatory drugs (NSAIDs); diclofenac potassium, ibuprofen and ketoprofen, successfully to treat COVID-19 patients. Furthermore, we agree with a recommendation that glucocorticoids should not be used routinely for COVID-19 patients and suggested to be beneficial only for patients with late acute respiratory distress syndrome. A clinical proof of ibuprofen safety in COVID-19 has been published by other researchers and we suggest that early administration of NSAIDs, including ibuprofen, in COVID-19 is not only safe but it might also prevent COVID-19 complications and this manuscript explains some of the suggested associated protective mechanisms.

Lymphopenic hospital acquired sepsis (L-HAS): An immunological phenotype conferring higher risk of mortality / Sepsis nosocomial linfopénica: un fenotipo inmunológico que confiere un mayor riesgo de mortalidad

No disponible

Calorie restriction induces reversible lymphopenia and lymphoid organ atrophy due to cell redistribution.

Calorie restriction (CR) without malnutrition increases life span and health span in multiple model organisms. In non-human and human primates, CR causes changes that protect against several age-related pathologies, reduces inflammation, and preserves or improves cell-mediated immunity. However, CR has also been shown to exhibit adverse effects on certain organs and systems, including the immune system, and to impact genetically different organisms of the same species differentially. Alternately, short periods of fasting followed by refeeding may result in the proliferation of bone marrow stem cells, suggesting a potential rejuvenation effect that could impact the hematopoietic compartment. However, the global consequences of CR followed by refeeding on the immune system have not been carefully investigated. Here, we show that individuals practicing long-term CR with adequate nutrition have markedly lower circulating levels of total leukocytes, neutrophils, lymphocytes, and monocytes. In 10-month-old mice, short-term CR lowered lymphocyte cellularity in multiple lymphoid tissues, but not in bone marrow, which appears to be a site of influx, or a "safe haven" for B, NK, and T cells during CR. Cellular loss and redistribution was reversed within the first week of refeeding. Based on BrdU incorporation and Ki67 expression assays, repopulating T cells exhibited high proliferation in the refeeding group following CR. Finally, we demonstrated that the thymus was not essential for T cell repopulation following refeeding. These findings are of potential relevance to strategies to rejuvenate the immune system in mammals and warrant further investigation.

Effect of Radiation Treatment Volume Reduction on Lymphopenia in Patients Receiving Chemoradiotherapy for Glioblastoma.

PURPOSE: To evaluate whether reduction in glioblastoma radiation treatment volume can reduce risk of acute severe lymphopenia (ASL). METHODS AND MATERIALS: A total of 210 patients with supratentorial/nonmetastatic glioblastoma were treated with radiation therapy (RT) plus temozolomide from 2007 to 2016 and had laboratory data on total lymphocyte counts. Before 2015, 164 patients were treated with standard-field RT (SFRT), and limited-field RT (LFRT) was implemented thereafter for 46 patients to reduce treatment volume. Total lymphocyte counts were evaluated at baseline, during RT, and at approximately week 12 from initiating RT. Acute severe lymphopenia was defined as any total lymphocyte count < 500 cells/µL within 3 months (by week 12) of initiating RT. Multivariate analysis for overall survival (OS) was performed with Cox regression and with logistic regression for ASL. Propensity score matching was performed to adjust for variability between cohorts. Acute severe lymphopenia, progression-free survival (PFS), and OS were compared using the Kaplan-Meier method. RESULTS: Limited-field RT patients had higher gross tumor volume than SFRT patients yet lower brain dose-volume parameters, including volume receiving 25 Gy (V25 Gy: 41% vs 53%, respectively, P < .01). Total lymphocyte count at week 12 was significantly higher for LFRT than for SFRT (median: 1100 cells/µL vs 900 cells/µL, respectively, P = .02). On multivariate analysis, ASL was an independent predictor of OS, and brain V25 Gy was an independent predictor of ASL. The ASL rate at 3 months was 15.5% for LFRT and 33.8% for SFRT (P = .12). In a propensity-matched comparison of 45 pairs of LFRT and SFRT patients, PFS (median: 5.9 vs 6.2 months, respectively, P = .58) and OS (median: 16.2 vs 13.9 months, respectively, P = .69) were not significantly different. CONCLUSIONS: Limited-field RT is associated with less lymphopenia after RT plus temozolomide and does not adversely affect PFS or OS. Brain V25 Gy is confirmed as an important dosimetric predictor for ASL.

Recent advances in radiation therapy of pancreatic cancer.

Pancreatic cancer has a dismal prognosis with an overall survival outcome of just 5% at five years. However, paralleling our improved understanding of the biology of pancreatic cancer, treatment paradigms have also continued to evolve with newer advances in surgical techniques, chemotherapeutic agents, radiation therapy (RT) techniques, and immunotherapy paradigms. RT dose, modality, fraction size, and sequencing are being evaluated actively, and the interplay between RT and immune effects has opened up newer avenues of research. In this review, we will emphasize recent advances in RT for pancreatic cancer, focusing on preoperative chemoradiation, RT dose escalation, sparing of the spleen to reduce lymphopenia, and combination of RT with immunotherapy.

Systemic Intravenous Adoptive Transfer of Autologous Lymphokine-activated αß T-Cells Improves Temozolomide-induced Lymphopenia in Patients with Glioma.

In this clinical study, we investigated the safety and clinical usefulness of systemic adoptive immunotherapy using autologous lymphokine-activated αß T-cells (αß T-cells), combined with standard therapies, in patients with malignant brain tumors. Twenty-three patients with different malignant brain tumors, consisting of 14 treated with temozolomide (TMZ group) and 9 treated without temozolomide (non-TMZ group), received systemic intravenous injections of αß T-cells (mean=10.4 injections/patient for the TMZ group, and 4.78 for the non-TMZ group). No significant adverse effects associated with the αß T-cell injection were observed, and the total lymphocyte count (TLC) improved significantly in the TMZ group after five injections. Furthermore, CD8-positive or T-cell receptor V gamma -positive cells were increased with TLC in three patients with glioblastoma multiforme. These findings suggest that systemic αß T-cell immunotherapy is well tolerated, and may help restore an impaired and imbalanced T-cell immune status, and temozolomide- and/or radiotherapy-induced lymphopenia. Future prospective study is needed to clarify the clinical merits of this immunotherapy.

MLF1 is a proapoptotic antagonist of HOP complex-mediated survival.

In the HAX1/HtrA2-OMI/PARL (HOP) mitochondrial protein complex, anti-apoptotic signals are generated by cleavage and activation of the serine protease HtrA2/OMI by the rhomboid protease PARL upon recruitment of both proteases to inner mitochondrial membrane protein HAX1 (HS1-associated protein X-1). Here we report the negative regulation of the HOP complex by human leukemia-associated myeloid leukemia factor 1 (MLF1). We demonstrate that MLF1 physically and functionally associates with HAX1 and HtrA2. Increased interaction of MLF1 with HAX1 and HtrA2 displaces HtrA2 from the HOP complex and inhibits HtrA2 cleavage and activation, resulting in the apoptotic cell death. Conversely, over-expressed HAX1 neutralizes MLF1's effect and inhibits MLF1-induced apoptosis. Importantly, Mlf1 deletion reverses B- and T-cell lymphopenia and significantly ameliorates the progressive striatal and cerebellar neurodegeneration observed in Hax1-/- mice, with a doubling of the lifespan of Mlf1-/-/Hax1-/- animals compared to Hax1-/- animals. Collectively, these data indicate that MLF1 serves as a proapoptotic antagonist that interacts with the HOP mitochondrial complex to modulate cell survival.

Red Wine Prevents the Acute Negative Vascular Effects of Smoking.

BACKGROUND: Moderate consumption of red wine is associated with fewer cardiovascular events. We investigated whether red wine consumption counteracts the adverse vascular effects of cigarette smoking. METHODS: Participants smoked 3 cigarettes alone or after drinking a titrated volume of red wine. Clinical chemistry, blood counts, plasma cytokine enzyme-linked immunosorbent assays, immunomagnetic separation of CD14+ monocytes for gene expression analysis, fluorescence-activated cell sorting for microparticles, and isolation of circulating mononuclear cells to measure telomerase activity were performed, and urine cotinine levels were quantified. RESULTS: Compared with baseline, leukocytosis (P = .019), neutrophilia (P <.001), lymphopenia (P <.001), and eosinopenia (P = .008) were observed after only smoking. Endothelial and platelet-, monocyte-, and leukocyte-derived microparticles (P <.001 each) were elevated. In monocytes, messenger RNA expression of interleukin (IL)-6 (2.6- ± 0.57-fold), tumor necrosis factor alpha (2.2- ± 0.62-fold), and IL-1b (2.3- ± 0.44-fold) were upregulated, as was IL-6 (1.2 ± 0.12-fold) protein concentration in plasma. Smoking acutely inhibited mononuclear cell telomerase activity. Markers of endothelial damage, inflammation, and cellular aging were completely attenuated by red wine consumption. CONCLUSION: Cigarette smoke results in acute endothelial damage, vascular and systemic inflammation, and indicators of the cellular aging processes in otherwise healthy nonsmokers. Pretreatment with red wine was preventive. The findings underscore the magnitude of acute damage exerted by cigarette smoking in "occasional lifestyle smokers" and demonstrate the potential of red wine as a protective strategy to avert markers of vascular injury.

Idiopathic CD4 lymphocytopenia.

BACKGROUND: Idiopathic CD4 lymphocytopenia (ICL) is a rare disorder of unknown etiology. Diagnostic criteria include a persistent CD4 T-cell lymphopenia with no underlying primary or secondary immune deficiencies and a CD4 T-cell count of 300 cells/mL or 20% total lymphocyte on multiple occasions. OBJECTIVE: To increase awareness of ICL and to provide a review of the clinical characteristics, diagnosis, and management of this disease process. Presently, many of these patients receive prophylactic treatment similar to other T-cell deficient conditions, most notably patients with human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome; however, the same indications may not necessarily apply to this patient population because the T cells are not affected by a virus as in HIV. METHODS: A literature search of salient articles that describe case reports and case series of ICL and their management were analyzed. RESULTS: A case of ICL with a literature review is presented with emphasis on clinical pearls and pitfalls. The patients with ICL are usually identified with a CD4 count of 200 cells/mL when complications develop. Opportunistic infections are the most common initial manifestations. Current therapies used to increase CD4 levels include interleukin 2, interferon gamma, interleukin 7, and allogeneic hematopoietic stem cell transplantation, with variable results. CONCLUSION: ICL is a diagnosis of exclusion when there is no identifiable underlying cause for a low CD4 count. Although the nature of the T-cell problem is not the same in ICL and HIV, in the absence of specific guidelines, patients receive the same prophylactic treatment as patients with HIV.

Lymphocyte-Sparing Effect of Stereotactic Body Radiation Therapy in Patients With Unresectable Pancreatic Cancer.

PURPOSE: Radiation-induced lymphopenia (RIL) is associated with inferior survival in patients with glioblastoma, lung cancer, and pancreatic cancer. We asked whether stereotactic body radiation therapy (SBRT) decreases severity of RIL compared to conventional chemoradiation therapy (CRT) in locally advanced pancreatic cancer (LAPC). METHODS AND MATERIALS: Serial total lymphocyte counts (TLCs) from patients enrolled in a prospective trial of SBRT for LAPC were compared to TLCs from an existing database of LAPC patients undergoing definitive CRT. SBRT patients received 33 Gy (6.6 Gy × 5 fractions). CRT patients received a median dose of 50.4 Gy (1.8 Gy × 28 fractions) with concurrent 5-fluorouracil (77%) or gemcitabine (23%) therapy. Univariate and multivariate analyses (MVA) were used to identify associations between clinical factors and post-treatment TLC and between TLC and survival. RESULTS: Thirty-two patients received SBRT and 101 received CRT. Median planning target volume (PTV) was smaller in SBRT (88.7 cm(3)) than in CRT (344.6 cm(3); P<.001); median tumor diameter was larger for SBRT (4.6 cm) than for CRT (3.6 cm; P=.01). SBRT and CRT groups had similar median baseline TLCs. One month after starting radiation, 71.7% of CRT patients had severe lymphopenia (ie, TLC <500 cells/mm(3) vs 13.8% of SBRT patients; P<.001). At 2 months, 46.0% of CRT patients remained severely lymphopenic compared with 13.6% of SBRT patients (P=.007). MVA demonstrated that treatment technique and baseline TLCs were significantly associated with post-treatment TLC at 1 but not 2 months after treatment. Higher post-treatment TLC was associated with improved survival regardless of treatment technique (hazard ratio [HR] for death: 2.059; 95% confidence interval: 1.310-3.237; P=.002). CONCLUSIONS: SBRT is associated with significantly less severe RIL than CRT at 1 month in LAPC, suggesting that radiation technique affects RIL and supporting previous modeling studies. Given the association of severe RIL with survival in LAPC, further study of the effect of radiation technique on immune status is warranted.

Switch-mediated activation and retargeting of CAR-T cells for B-cell malignancies.

Chimeric antigen receptor T (CAR-T) cell therapy has produced impressive results in clinical trials for B-cell malignancies. However, safety concerns related to the inability to control CAR-T cells once infused into the patient remain a significant challenge. Here we report the engineering of recombinant antibody-based bifunctional switches that consist of a tumor antigen-specific Fab molecule engrafted with a peptide neo-epitope, which is bound exclusively by a peptide-specific switchable CAR-T cell (sCAR-T). The switch redirects the activity of the bio-orthogonal sCAR-T cells through the selective formation of immunological synapses, in which the sCAR-T cell, switch, and target cell interact in a structurally defined and temporally controlled manner. Optimized switches specific for CD19 controlled the activity, tissue-homing, cytokine release, and phenotype of sCAR-T cells in a dose-titratable manner in a Nalm-6 xenograft rodent model of B-cell leukemia. The sCAR-T-cell dosing regimen could be tuned to provide efficacy comparable to the corresponding conventional CART-19, but with lower cytokine levels, thereby offering a method of mitigating cytokine release syndrome in clinical translation. Furthermore, we demonstrate that this methodology is readily adaptable to targeting CD20 on cancer cells using the same sCAR-T cell, suggesting that this approach may be broadly applicable to heterogeneous and resistant tumor populations, as well as other liquid and solid tumor antigens.

Versatile strategy for controlling the specificity and activity of engineered T cells.

The adoptive transfer of autologous T cells engineered to express a chimeric antigen receptor (CAR) has emerged as a promising cancer therapy. Despite impressive clinical efficacy, the general application of current CAR-T--cell therapy is limited by serious treatment-related toxicities. One approach to improve the safety of CAR-T cells involves making their activation and proliferation dependent upon adaptor molecules that mediate formation of the immunological synapse between the target cancer cell and T-cell. Here, we describe the design and synthesis of structurally defined semisynthetic adaptors we refer to as "switch" molecules, in which anti-CD19 and anti-CD22 antibody fragments are site-specifically modified with FITC using genetically encoded noncanonical amino acids. This approach allows the precise control over the geometry and stoichiometry of complex formation between CD19- or CD22-expressing cancer cells and a "universal" anti-FITC-directed CAR-T cell. Optimization of this CAR-switch combination results in potent, dose-dependent in vivo antitumor activity in xenograft models. The advantage of being able to titrate CAR-T-cell in vivo activity was further evidenced by reduced in vivo toxicity and the elimination of persistent B-cell aplasia in immune-competent mice. The ability to control CAR-T cell and cancer cell interactions using intermediate switch molecules may expand the scope of engineered T-cell therapy to solid tumors, as well as indications beyond cancer therapy.

Selective Treg reconstitution during lymphopenia normalizes DC costimulation and prevents graft-versus-host disease.

Regulatory T cells (Tregs) have been shown to enhance immune reconstitution and prevent graft-versus-host disease (GVHD) after hematopoietic stem cell transplantation; however, it is unclear how Tregs mediate these effects. Here, we developed a model to examine the mechanism of Treg-dependent regulation of immune reconstitution. Lymphopenic mice were selectively reconstituted with Tregs prior to transfer of conventional CD4+ T cells. Full Treg reconstitution prevented the rapid oligoclonal proliferation that gives rise to pathogenic CD4 effector T cells, while preserving the slow homeostatic form of lymphopenia-induced peripheral expansion that repopulates a diverse peripheral T cell pool. Treg-mediated CTLA-4-dependent downregulation of CD80/CD86 on DCs was critical for inhibition of rapid proliferation and was a function of the Treg/DC ratio achieved by reconstitution. In an allogeneic BM transplant model, selective Treg reconstitution before T cell transfer also normalized DC costimulation and provided complete protection against GVHD. In contrast, cotransfer of Tregs was not protective. Our results indicate that achieving optimal recovery from lymphopenia should aim to improve early Treg reconstitution in order to increase the relative number of Tregs to DCs and thereby inhibit spontaneous oligoclonal T cell proliferation.

Modulation of inflammation and pathology during dengue virus infection by p38 MAPK inhibitor SB203580.

Dengue virus (DENV) infection could lead to dengue fever (DF), dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS). The disease outcome is controlled by both viral and host factors. Inflammation mediators from DENV-infected cells could contribute to increased vascular permeability, leading to severe DHF/DSS. Therefore, suppression of inflammation could be a potential therapeutic approach for treatment of dengue patients. In this context, p38 MAPK (mitogen-activated protein kinase) is a key enzyme that modulates the initiation of stress and inflammatory responses. Here we show that SB203580, a p38 MAPK inhibitor, suppressed the over production of DENV-induced pro-inflammatory mediators such as TNF-α, IL-8, and RANTES from human PBMCs, monocytic THP-1, and granulocyte KU812 cell lines. Oral administration of SB203580 in DENV-infected AG129 mice prevented hematocrit rise and lymphopenia, limited the development of inflammation and pathology (including intestine leakage), and significantly improved survival. These results, for the first time, have provided experimental evidence to imply that a short term inhibition of p38 MAPK may be beneficial to reduce disease symptoms in dengue patients.

Ischemic postconditioning protects against focal cerebral ischemia by inhibiting brain inflammation while attenuating peripheral lymphopenia in mice.

BACKGROUND: Ischemic postconditioning (IPostC) has been shown to attenuate brain injury in rat stroke models, but a mouse model has not been reported. This study establishes an IPostC model in mice and investigates how IPostC affects infiltration of leukocytes in the ischemic brain and lymphopenia associated with stroke-induced immunodepression. MATERIAL AND METHODS: A total of 125 mice were used. IPostC was performed by a repeated series of brief occlusions of the middle cerebral artery (MCA) after reperfusion, in a focal ischemia model in mice. Infarct sizes, neurological scores, inflammatory brain cells and immune cell populations in lymph nodes, spleen and bone marrow were analyzed with fluorescence-activated cell sorting (FACS). RESULTS: IPostC performed immediately, 2 min and 3 h after reperfusion significantly reduced infarct sizes and attenuated neurological scores as measured up to 3 days post-stroke. In the group with strongest protection, infarct sizes were reduced from 49.6±2.8% (n=16) to 27.9±2.9% (n=10, P<.001). The spared infarct areas were seen in the ischemic penumbra or ischemic margins, i.e., the border zones between the cortical territories of the anterior cerebral artery and those of the MCA, as well as in the ventromedial and dorsolateral striata. FACS analyses showed that IPostC significantly blocked increases in the numbers of microglia (CD45intCD11b+), macrophages (CD45hiCD68+), CD4 T cells (CD45+CD4+) and CD8 T cells (CD45+CD8+) as well as B lymphocytes (CD45+CD19+) in the ischemic brain (n=5/group). Reduced-immune cell numbers in the peripheral blood and spleen were increased by IPostC while immune cell populations in the bone marrow were not altered by IPostC. CONCLUSIONS: IPostC reduced brain infarction and mitigated neurological deficits in mice, likely by blocking infiltration of both innate and adaptive immune cells in the ischemic brain. In addition, IPostC robustly attenuated peripheral lymphopenia and thus improved systemic immunodepression.