Joseph L. Bobadilla

IL-17–dependent cellular immunity to collagen type V predisposes to obliterative bronchiolitis in human lung transplants

Bronchiolitis obliterans syndrome (BOS), a process of fibro-obliterative occlusion of the small airways in the transplanted lung, is the most common cause of lung transplant failure. We tested the role of cell-mediated immunity to collagen type V [col(V)] in this process. PBMC responses to col(II) and col(V) were monitored prospectively over a 7-year period. PBMCs from lung transplant recipients, but not from healthy controls or col(IV)-reactive Goodpastures syndrome patients after renal transplant, were frequently col(V) reactive. Col(V)-specific responses were dependent on both CD4+ T cells and monocytes and required both IL-17 and the monokines TNF-alpha and IL-1beta. Strong col(V)-specific responses were associated with substantially increased incidence and severity of BOS. Incidences of acute rejection, HLA-DR mismatched transplants, and induction of HLA-specific antibodies in the transplant recipient were not as strongly associated with a risk of BOS. These data suggest that while alloimmunity initiates lung transplant rejection, de novo autoimmunity mediated by col(V)-specific Th17 cells and monocyte/macrophage accessory cells ultimately causes progressive airway obliteration.

Microchimerism is strongly correlated with tolerance to noninherited maternal antigens in mice

In mice and humans, the immunologic effects of developmental exposure to noninherited maternal antigens (NIMAs) are quite variable. This heterogeneity likely reflects differences in the relative levels of NIMA-specific T regulatory (T(R)) versus T effector (T(E)) cells. We hypothesized that maintenance of NIMA-specific T(R) cells in the adult requires continuous exposure to maternal cells and antigens (eg, maternal microchimerism [MMc]). To test this idea, we used 2 sensitive quantitative polymerase chain reaction (qPCR) tests to detect MMc in different organs of NIMA(d)-exposed H2(b) mice. MMc was detected in 100% of neonates and a majority (61%) of adults; nursing by a NIMA+ mother was essential for preserving MMc into adulthood. MMc was most prevalent in heart, lungs, liver, and blood, but was rarely detected in unfractionated lymphoid tissues. However, MMc was detectable in isolated CD4+, CD11b+, and CD11c+ cell subsets of spleen, and in lineage-positive cells in heart. Suppression of delayed type hypersensitivity (DTH) and in vivo lymphoproliferation correlated with MMc levels, suggesting a link between T(R) and maternal cell engraftment. In the absence of neonatal exposure to NIMA via breastfeeding, MMc was lost, which was accompanied by sensitization to NIMA in some offspring, indicating a role of oral exposure in maintaining a favorable T(R) > T(E) balance.

Th-17, Monokines, Collagen Type V, and Primary Graft Dysfunction in Lung Transplantation

RATIONALE The pathogenesis of primary graft dysfunction (PGD), a serious complication of lung transplantation, is poorly understood. Human studies and rodent models have shown that collagen type V (col[V]), stimulates IL-17-dependent cellular immunity after lung transplantation. OBJECTIVES To determine whether patients with end-stage lung disease develop pretransplant col(V)-specific cellular immunity, and if so, the impact of this response on PGD. METHODS Trans-vivo delayed-type hypersensitivity (TV-DTH) assays were used to evaluate memory T-cell responses to col(V) in 55 patients awaiting lung transplantation. Pa(O(2))/Fi(O(2)) index data were used to assess PGD. Univariate risk factor analysis was performed to identify variables associated with PGD. Rats immunized with col(V) or irrelevant antigen underwent lung isografting to determine if prior anti-col(V) immunity triggers PGD in the absence of alloreactivity. MEASUREMENTS AND MAIN RESULTS We found that 58.8% (10/17) of patients with idiopathic pulmonary fibrosis, and 15.8% (6/38) of patients without idiopathic pulmonary fibrosis tested while on the wait list for a lung transplant were col(V) DTH positive. Col(V) reactivity was CD4(+) T-cell and monocyte mediated, and dependent on IL-17, IL-1beta, and tumor necrosis factor (TNF)-alpha. Pa(O(2))/Fi(O(2)) indices were impaired significantly 6-72 hours after transplantation in col(V)-reactive versus nonreactive patients. Univariate risk factor analysis identified only preoperative TV-DTH to col(V) and ischemic time as predictors of PGD. Finally, in a rat lung isograft model, col(V) sensitization resulted in significantly lower Pa(O(2))/Fi(O(2)), increased local TNF-alpha and IL-1beta production, and a moderate-to-severe bronchiolitis/vasculitis when compared with control isografts. CONCLUSIONS The data suggest that activation of innate immunity by col(V)-specific Th-17 memory cells represents a novel pathway to PGD after lung transplantation.

Developmental Exposure to Noninherited Maternal Antigens Induces CD4+ T Regulatory Cells: Relevance to Mechanism of Heart Allograft Tolerance

We hypothesize that developmental exposure to noninherited maternal Ags (NIMA) results in alloantigen-specific natural and adaptive T regulatory (TR) cells. We compared offspring exposed to maternal H-2d (NIMAd) with nonexposed controls. In vitro assays did not reveal any differences in T cell responses pretransplant. Adoptive transfer assays revealed lower lymphoproliferation and greater cell surface TGF-β expression on CD4+ T cells of NIMAd-exposed vs control splenocytes. NIMAd-exposed splenocytes exhibited bystander suppression of tetanus-specific delayed-type hypersensitivity responses, which was reversed with Abs to TGF-β and IL-10. Allospecific T effector cells were induced in all mice upon i.v. challenge with B6D2F1 splenocytes or a DBA/2 heart transplant, but were controlled in NIMAd-exposed mice by TR cells to varying degrees. Some (40%) NIMAd-exposed mice accepted a DBA/2 allograft while others (60%) rejected in delayed fashion. Rejector and acceptor NIMAd-exposed mice had reduced T effector responses and increased Foxp3+ TR cells (CD4+CD25+Foxp3+ TR) in spleen and lymph nodes compared with controls. The key features distinguishing NIMAd-exposed acceptors from all other mice were: 1) higher frequency of IL-10- and TGF-β-producing cells primarily in the CD4+CD25+ T cell subset within lymph nodes and allografts, 2) a suppressed delayed-type hypersensitivity response to B6D2F1 Ags, and 3) allografts enriched in LAP+, Foxp3+, and CD4+ T cells, with few CD8+ T cells. We conclude that the beneficial NIMA effect is due to induction of NIMA-specific TR cells during ontogeny. Their persistence in the adult, and the ability of the host to mobilize them to the graft, may determine whether NIMA-specific tolerance is achieved.

The effect of warfarin therapy on endoleak development after endovascular aneurysm repair (EVAR) of the abdominal aorta

OBJECTIVES The presence of an endoleak after endovascular abdominal aortic aneurysm (AAA) repair (EVAR) may predispose to sac expansion and potential sac rupture. The incidence of endoleak after AAA repair can be as high as 20% to 30%. We investigated whether warfarin anticoagulation was an independent risk factor for endoleak after EVAR for AAA. METHODS All AAA patients who underwent elective EVAR were prospectively followed-up. Data for demographics, clinical comorbidities, outcomes, EVAR devices, and anticoagulation methods were recorded. All patients underwent routine follow-up at 1, 6, and 12 months and annually thereafter. Computed tomography angiography (CTA) with 3-dimensional (3D) volumetric analysis was also completed. RESULTS During a 7-year period, 127 consecutive patients with infrarenal AAAs who underwent EVAR were monitored for a mean of 2.14 years. The average age at the time of EVAR was 73.8 years. Warfarin therapy alone was administered to 24 patients, and anticoagulation with antiplatelet therapy alone was administered to 103. During the study period, 38 (29.9%) endoleaks were documented. The overall endoleak rate was 13 of 24 in the warfarin group and 25 of 103 in the antiplatelet group (P = .004). CTA 3D volumetric aneurysm sac analysis showed an increase of 16.09% in the warfarin study group and a reduction of 9.71% in the antiplatelet group (P = .04). CONCLUSIONS Anticoagulation with warfarin appears to be linked to an increased risk for the development of endoleak after EVAR, specifically type II. Volumetric analysis showed warfarin therapy also contributed to persistent aneurysm sac expansion. These data suggest that patients who require warfarin anticoagulation for other indications should be advised that they might be at an increased risk for the development of endoleaks, subsequent secondary interventions, persistent sac expansion, and possible delayed sac rupture.

Interleukin-17-dependent autoimmunity to collagen type v in atherosclerosis

Rationale: Considerable evidence shows atherosclerosis to be a chronic inflammatory disease in which immunity to self-antigens contributes to disease progression. We recently identified the collagen type V [col(V)] &agr;1(V) chain as a key autoantigen driving the Th17-dependent cellular immunity underlying another chronic inflammatory disease, obliterative bronchiolitis. Because specific induction of &agr;1(V) chains has previously been reported in human atheromas, we postulated involvement of col(V) autoimmunity in atherosclerosis. Objective: To determine whether col(V) autoimmunity may be involved in the pathogenesis of atherosclerosis. Methods and Results: Here, we demonstrate Th17-dependent anti-col(V) immunity to be characteristic of atherosclerosis in human coronary artery disease (CAD) patients and in apolipoprotein E–null (ApoE−/−) atherosclerotic mice. Responses were &agr;1(V)-specific in CAD with variable Th1 pathway involvement. In early atherosclerosis in ApoE−/− mice, anti-col(V) immunity was tempered by an interleukin (IL)-10–dependent mechanism. In support of a causal role for col(V) autoimmunity in the pathogenesis of atherosclerosis, col(V) sensitization of ApoE−/− mice on a regular chow diet overcame IL-10–mediated inhibition of col(V) autoimmunity, leading to increased atherosclerotic burden in these mice and local accumulation of IL-17–producing cells, particularly in the col(V)-rich adventitia subjacent to the atheromas. Conclusions: These findings establish col(V) as an autoantigen in human CAD and show col(V) autoimmunity to be a consistent feature in atherosclerosis in humans and mice. Furthermore, data are consistent with a causative role for col(V) in the pathogenesis of atherosclerosis.

Reflux-Induced Collagen Type V Sensitization: Potential Mediator of Bronchiolitis Obliterans Syndrome

BACKGROUND Lung transplantation continues to have poor long-term survival partly because of the high incidence of bronchiolitis obliterans syndrome (BOS). Gastroesophageal reflux disease (GERD) has been implicated in BOS pathogenesis. We investigated the role of collagen type V [col(V)] sensitization in this process. METHODS Only primary lung transplant recipients were included. Reflux status was assessed with pH monitoring, impedance plethysmography, and esophagogastroduodenoscopy. Sensitivity to col(V) was determined with trans vivo delayed-type hypersensitivity reaction (DTH). Kaplan-Meier analyses were performed. RESULTS Of the 54 recipients, 26 had proven GERD. There were no significant between-group differences in diagnosis; donor and recipient age; sex; ischemic time; single vs bilateral; human leukocyte antigen A, B, and DR matching cytomegalovirus status; acute rejections; or mean follow-up period. The mean DTH response in the GERD group was 25.7 x 10(-4) inches vs 18.3 x 10(-4) inches in the non-GERD group (P = .023). There was a significant reduction in BOS-free survival in the GERD group for both BOS-I (GERD+, 28.3%; GERD-, 86.6%; P = .0001) and BOS-II/III (GERD+, 66.2%; GERD-, 91.7%; P = .0374). A second cohort of 53 patients awaiting lung transplantation also was assayed. The mean DTH response in the GERD group was 24.0 x 10(-4) inches vs 13.1 x 10(-4) inches in the non-GERD group (P = .003). There were no differences in age or sex. CONCLUSIONS GERD is strongly associated with the development of BOS after primary lung transplantation. Col(V) sensitization is associated with reflux and BOS and may play an intermediary role in the pathogenesis of BOS. Trials using col(V) reactivity to assess the impact of antireflux procedures in patients with lung transplantation and idiopathic pulmonary fibrosis are warranted.

Multidisciplinary approach decreases length of stay and reduces cost for ventricular assist device therapy

High implantation costs and long postoperative length of stay (LOS) in debilitated patients complicate ventricular assist device (VAD) therapy. Between July 2000 and February 2005, 30 patients received a VAD at our institution. Of those, 20 patients were successfully discharged from the hospital with VADs. In August 2003, a multidisciplinary team was formed consisting of all services for VAD patients to replace a single-discipline (cardiac surgery) system. This team evaluated potential VAD candidates and identified optimal timing for implantation. These 20 VAD patients were divided into two groups according to the initiation of multidisciplinary team; the traditional group (n=7, July 2000-July 2003) and the multidisciplinary group (n=13, August 2003-February 2005). Patient demographics were not different. The LOS decreased from 61 to 15 days (P<0.01), especially LOS on the floor decreased from 35 to 7 days (P=0.03). The floor cost was significantly reduced (

Clinical Implications of Non–Contrast-Enhanced Computed Tomography for Follow-Up After Endovascular Abdominal Aortic Aneurysm Repair

47,111 vs.

Interleukin-17–Dependent Autoimmunity to Collagen Type V in AtherosclerosisNovelty and Significance

8742, P<0.01), leading to a decrease in total postoperative cost (