Chemokine receptors--future therapeutic targets for HIV?

To date, triple drug therapies for HIV have resulted in spectacular reductions in the number of virus particles and often remarkable recovery from disease in infected people. There is still, however, a great need for improved therapies. A battery of drugs aimed at different stages in the life cycle of HIV will enable switching of treatments if resistant viruses emerge or if patients are unable to tolerate particular therapies. Intense efforts are now underway to produce drugs that target chemokine receptors used by HIV to gain entry into cells. HIV needs two receptors on the host cell surface for efficient attachment and infection. HIV first interacts with CD4 but requires a coreceptor to penetrate the cell membrane. The first coreceptor, identified in 1996, is a member of the family of chemokine receptors, members of the G-protein coupled 7TM superfamily, which are involved in the trafficking of leukocytes in immune surveillance and inflammation. Such a therapeutic approach would differ from those used successfully to date, which focus largely on proteins coded by the HIV virus itself, and which are required for the replicative cycle of the virus. Many small, orally bioavailable molecules that block various 7TM receptors are used to treat a panoply of diseases including ulcers, allergies, migraines, and schizophrenia. These molecules are the cornerstone of the pharmaceutical industry's contribution to the fight against so many diseases, and it is hoped that a small molecule inhibitor of coreceptors can be developed that will become an invaluable drug in the fight against AIDS.     

Treatment and outcomes of acute myocardial infarction among patients of cardiologists and generalist physicians

BACKGROUND: Both cardiologists and generalist physicians care for patients with acute myocardial infarction, but little is known about their patients' characteristics, treatments, and outcomes. METHODS: We identified attending and consulting physicians, patient characteristics, drugs, procedures, and mortality from clinical and administrative records of 1620 Medicare beneficiaries aged 65 to 79 years who were treated for acute myocardial infarction at 285 hospitals in Texas during 1990. RESULTS: Patients treated by attending cardiologists were younger, had prior congestive heart failure less frequently, and were initially treated in hospitals offering coronary angioplasty or bypass surgery more often than patients treated by attending generalist physicians (for each, P<.004). Adjusting for patient and hospital characteristics, cardiologists were more likely than generalist physicians to prescribe thrombolytic therapy and aspirin (P<.05) but not beta-adrenergic blocking agents (beta-blockers). Cardiologists used coronary angiography and angioplasty more often (P<.003), but not echocardiography or exercise testing. Adjusted 1-year mortality did not differ significantly between patients of attending cardiologists and generalist physicians (odds ratio, 1.01; 95% confidence interval, 0.76-1.35) or between patients of generalist physicians with and without a consulting cardiologist (odds ratio, 0.83; 95% confidence interval, 0.60-1.16). However, patients initially admitted to hospitals offering coronary angioplasty and bypass surgery had lower adjusted 1-year mortality than patients admitted to other hospitals (odds ratio, 0.68; 95% confidence interval, 0.47-0.98). CONCLUSIONS: Compared with generalist physicians, cardiologists used some, but not all, effective drugs more frequently, as well as coronary angiography and angioplasty. Although these differences were not associated with lower adjusted mortality among cardiologists' patients, cardiologists were more likely to treat patients in hospitals with better outcomes. Future studies should identify organizational factors that improve outcomes of myocardial infarction.     

Human immunodeficiency virus and hepatitis B virus seroprevalence in an urban trauma population

OBJECTIVE: To determine the seroprevalence of the human immunodeficiency virus (HIV) and the hepatitis B virus (HBV) in patients of an urban level I trauma center. DESIGN: Prospective, blinded point prevalence study of serum HIV and HBV antibody and antigen. SETTING: An urban level I trauma center that participates in a trauma system serving three million people. PATIENTS: The study included 994 (94.8%) of 1049 consecutive trauma service patients treated between June 6, 1988 and September 22, 1988. The patients were 82.2% male and 73.1% black, with a mean age of 28.8 +/- 12.3 years. Blunt trauma was seen in 65.4% of patients, 5.2% were in shock, and 96.2% survived their trauma. MAIN OUTCOME MEASURES: HIV and HBV seroprevalence, using both antibody and antigen testing. RESULTS: HIV infection was seen in 43 patients (4.3%); 41 (95.3%) were HIV Ab+ and two (4.7%) were HIV Ab-/HIV Ag+. Infection with the HBsAg was seen in 31 patients (3.1%). Infection with either virus was seen in 70 patients (7%); four patients (0.4%) were infectious for both viruses. Infection was related to age 20 to 49 years, i.v. drug use, a hepatitis or sexually transmitted disease history, prior HIV testing, shock, and death (p < 0.05). Penetrating trauma was not predictive of infection. In a logistic regression model, IV drug use was the single significant predictor of infection (p < 0.05). CONCLUSIONS: Young urban trauma patients, because of drug-related intentional violence, are 15.3 to 17.6 times more likely to be HIV infected and 3.9 to 7.9 times more likely to be infectious for HIV or HBV than the trauma population overall. The 12 to 21% infection rates in critically injured patients who require shock resuscitation and/or die reinforces the need for mandated universal precautions and for clear policies which govern the performance of procedures by physicians in training. Primary HIV infection in critically injured patients may worsen their outcome and may adversely affect the exposed health care worker. Emergency departments and trauma units should develop a referral system to HIV primary care services (HIV counselling and testing) for high risk patients and for adversely exposed health care workers.     

Neurologic manifestations of HIV infection. Using imaging studies and antiviral therapy effectively

Patients with HIV infection are at risk for neurologic complications that can arise through various means. Nervous system disorders sometimes occur as a direct consequence of the HIV infection itself. Or, as immunodeficiency progresses, patients can become susceptible to numerous opportunistic infections and other conditions that have neurologic involvement. Even the antiviral drugs used to treat HIV infection can induce neurologic manifestations. Dr Rachlis discusses several of these manifestations and their management.     

Do physicians discuss HIV and AIDS with patients? A survey of physician practices

HIV and AIDS continue to be major concerns to the health care community and the world around them. Preventive efforts and education have been the focus of the fight against AIDS thus far. By the year 2000, 75% of physicians are expected to conduct risk-reduction counseling for patients regularly. Previous studies show that a smaller percentage "routinely" follow this recommendation. The purpose of our study was to assess with what percentage of patients physicians discuss several HIV/ AIDS-related topics, what percentage of their patients are considered at risk for infection, and how comfortable the physicians are with their knowledge level and discussing the subject matter. We sent surveys to the last five graduating classes from St. Louis University School of Medicine and to 169 physician preceptors in the community. The survey asked about patients considered at risk, physician comfort level with HIV/ AIDS, the percentage of patients they discuss various HIV/AIDS topics with, and his or her preparedness for these discussions. Total responses were 464 (53.7%) representing all areas of medicine. Most of the physicians (72.9%) consider 0-25% of their patients at risk for HIV/AIDS. Eighty-one percent claim they are moderately or very comfortable discussing the material with patients and more than 90% feel they have at least adequate knowledge. Most of the respondents discuss the HIV/ AIDS topics with 0-25% of patients. Recent medical school graduates and primary care physicians are more comfortable with HIV/AIDS and discuss the surveyed topics with a higher percentage of patients.     

Cystic prostatic disease associated with adrenocortical lesions in the ferret (Mustela putorius furo)

CONTEXT: In British Columbia, human immunodeficiency virus (HIV)-infected persons eligible for antiretroviral therapy may receive it free but the extent to which HIV-infected injection drug users access it is unknown. OBJECTIVE: To identify patient and physician characteristics associated with antiretroviral therapy utilization in HIV-infected injection drug users. DESIGN: Prospective cohort study with record linkage between survey data and data from a provincial HIV/AIDS (acquired immunodeficiency syndrome) drug treatment program. SETTING: British Columbia, where antiretroviral therapies are offered free to all persons with HIV infection with CD4 cell counts less than 0.50 x 10(9)/L (500/microL) and/or HIV-1 RNA levels higher than 5000 copies/mL. SUBJECTS: A total of 177 HIV-infected injection drug users eligible for antiretroviral therapy, recruited through the prospective cohort study since May 1996. MAIN OUTCOME MEASURES: Patient use of antiretroviral drugs through the provincial drug treatment program and physician experience treating HIV infection. RESULTS: After a median of 11 months after first eligibility, only 71 (40%) of 177 patients had received any antiretroviral drugs, primarily double combinations (47/71 [66%]). Both patient and physician characteristics were associated with use of antiretroviral drugs. After adjusting for CD4 cell count and HIV-1 RNA level at eligibility, odds of not receiving antiretrovirals were increased more than 2-fold for females (odds ratio [OR], 2.53; 95% confidence interval [CI], 1.08-5.93) and 3-fold for those not currently enrolled in drug or alcohol treatment programs (OR, 3.49; 95% CI, 1.45-8.40). Younger drug users were less likely to receive therapy (OR, 0.47/10-y increase; 95% CI, 0.28-0.80). Those with physicians having the least experience treating persons with HIV infection were more than 5 times less likely to receive therapy (OR, 5.55; 95% CI, 2.49-12.37). CONCLUSIONS: Despite free antiretroviral therapy, many HIV-infected injection drug users are not receiving it. Public health efforts should target younger and female drug users, and physicians with less experience treating HIV infection.     

Occult HIV infection: diagnosis and treatment of older patients

The decrease in immune status that accompanies normal aging leaves individuals age 50 and older increasingly susceptible to the two main modes of HIV infection: sexual activity and blood transfusions. Although therapy for older HIV patients is essentially the same as for younger patients, knowledge of appropriate drug dosages and nutritional issues that influence the care of the older HIV patient is essential for physicians treating this population. Physicians need to recognize the clinical features of HIV-related dementia and opportunistic infections that distinguish it from other age-related illnesses such as Alzheimer's and Parkinson's disease. Known risk factors that affect older patients should influence physicians to routinely include HIV in their differential diagnoses.     

Use of carprofen for the treatment of pain and inflammation in dogs

Most studies of nonsteroidal anti-inflammatory drugs (NSAID) do not demonstrate appreciable differences in efficacy. As awareness of the adverse effects associated with NSAID use increases, safety is becoming the primary concern among physicians when selecting NSAID for use by their human patients. However, veterinarians may be less aware of the safety concerns associated with NSAID use. A wide range of NSAID is used to treat human beings with osteoarthrits; however, it is imperative to remember that dogs are especially sensitive to these drugs, and reports of serious, and occasionally fatal, complications are numerous. Carprofen is a propionic acid-derived NSAID that has anti-inflammatory, analgesic, and antipyretic activity. In animals, carprofen is as potent as indomethacina and more potent than aspirin or phenlbutazone, but carprofen appears to be safer than most other NSAID.     

Immunotherapy for Epstein-Barr virus-associated cancers

Epstein-Barr virus (EBV)-associated lymphoproliferative disease (EBV-LPD) is a frequently fatal complication of organ transplantation and human immunodeficiency virus (HIV) infection. We have studied the safety and efficacy of adoptively transferred, gene-marked virus-specific cytotoxic T lymphocytes (CTLs) as prophylaxis and treatment of EBV-LPD in recipients of T-cell-depleted allogeneic bone marrow. In 42 patients treated prophylactically, no toxicity was experienced. None of these patients developed EBV-LPD, in contrast with eight of 53 (15%) patients who did not receive prophylactic CTL. Three patients who had not received CTL developed aggressive disease and received CTL as treatment. Gene-marked CTL homed to tumor sites and selective accumulation of marker gene was detected in tumor tissues. Tumors regressed completely in two patients, but the third died of respiratory failure. Infused CTLs persisted for up to 3 years in vivo, they rapidly reconstituted EBV-specific immune responses to levels seen in normal individuals, and they reduced high viral titers by two to three logs. We are now using autologous EBV-specific CTL to treat patients with relapsed EBV-positive Hodgkin's disease and we are developing methods for the generation of antigen-specific lines. This approach could be applied to patients with HIV who develop EBV-LPD, using CTL derived early in the course of HIV infection.     

Intestinal absorption and biliary secretion of cholesterol in rats with nephrotic syndrome

STUDY OBJECTIVE: To evaluate physician prescribing practices for the initial therapy for tuberculosis (TB) according to the recommendations of the Centers for Disease Control and Prevention (CDC) and American Thoracic Society (ATS). DESIGN: Cross-sectional study. SETTING: Statewide TB surveillance system in New Jersey, 1994 to 1995. PATIENTS: We studied 1,230 culture-positive TB patients who were alive at diagnosis and whose isolates were tested for isoniazid susceptibility. RESULTS: Almost all TB patients (98%) were reported from counties with an isoniazid-resistant proportion of 4% or more, which is the minimum level for implementation of an initial four-drug regimen recommended by CDC/ATS. Overall, 36% of the 1,230 patients were not initially treated with four or more drugs. Multivariate analyses found that non-Hispanic white patients were more likely to be treated with fewer than four drugs than were non-Hispanic black patients. Private practitioners and physicians at chest clinics were about five times more likely to prescribe fewer than four drugs initially than were physicians at the hospital where a national TB center is located. CONCLUSION: A substantial proportion of physicians did not initially treat their TB patients according to the CDC/ATS recommendations. The results suggest that New Jersey physicians should be better informed about the recommendation and the high level of drug resistance in the communities they serve to assure that TB patients receive appropriate initial therapy.     

The medical setting: is it beyond the psychiatrist?

Total amounts of antimicrobial drugs used to treat inpatients during 1975 were calculated for three Canadian general hospitals, one of them the principal teaching hospital of a medical school. Use of drugs was compared with that reported for Boston City Hospital during periods when antimicrobial therapy was and was not supervised by infectious disease consultants. Ampicillin, tetracyclines, cephalosporins, erythromycin and aminoglycosides for prophylactic oral administration were used excessively in the three hospitals. The degree of overuse was comparable to that at Boston City Hospital during years when drug use was uncontrolled. Overuse or improper choice of antimicrobial drug decreases the quality of patient care and increases its cost. More rigorous education is needed for both medical students and practising physicians in the rational use of antimicrobial drugs. Informal consultation with an infectious disease unit should be required before certain overly popular or toxic antibiotics are administered to hospitalized patients.     

Wear of visible light-cured restorative materials and removable partial denture direct retainers

Parenteral nutrition is a part of the nutritional support regimen of patients with AIDS-associated wasting syndrome and gastrointestinal dysfunction. The cholesterol (CHOL) level in human immunodeficiency virus (HIV) membrane is very high, and recent lipid formulations with high phospholipid (PL) content have demonstrated the ability to trap CHOL from endogenous sources, modifying the composition of cell membranes. We administered lipid-based home parenteral nutrition for 3 mo to malnourished AIDS patients. The patients were randomly divided into two groups: 23 received the regular 20% fat emulsion formulation, and 27 received a 2% formulation enriched 10-fold with PLs but containing the same amount of triglycerides. All patients gained weight and improved their activity level. Those receiving the high-PL composition showed increased serum CHOL concentrations (from 147 to 241 mg/dL; P < 0.01), but no increase was seen in the number of CD4 cells or improvement in immune function. HIV infectivity was not modified. Patients receiving regular PLs had significantly decreased (P < 0.02) IgA concentrations (from 776 to 300 mg/dL) and improved mitogen response to phytohemagglutinin and to concanavalin A. This formula, too, had no effect on HIV infectivity. We conclude that standard parenteral nutritional influences the nutritional and immune status of malnourished AIDS patients. A PL-enriched parenteral formulation can trap CHOL, but it does not affect the immune profile or HIV infectivity in patients with advanced disease.     

Cartesian coordinate analysis of viral burden and CD4+ T-cell count in human immunodeficiency virus type-1 infection

Infection with the human immunodeficiency virus (HIV) and the subsequent derangement of host immunity place affected patients at risk for secondary infections. Some of the secondary pathogens occur with such frequency or are so rare in the non-immunosuppressed population that they have become part of the Centers for Disease Control and Prevention (CDC) classification for HIV/acquired immune deficiency syndrome (AIDS). Other infectious agents not yet included in the CDC definition are being reported in the HIV-infected population with increased frequency. General observations of the degree of immunosuppression associated with specific secondary infections have been useful in developing classification systems for HIV disease such as that of the CDC. However, the specific alterations in host immunity that promote infection with specific secondary pathogens are generally unknown. Geographic differences in the types and frequency of secondary infections also have been reported. Variation in strains of HIV, effect of malnutrition, lack of appropriate medical treatment, prevalence of virulent infectious diseases, and epidemiologic differences are possible contributing factors. Some infections that seemed likely to be closely associated with HIV infection have not occurred more frequently in HIV-infected patients. This review summarizes the histopathology of infectious conditions in the current CDC classification and highlights some conditions seen in HIV-infected individuals that are not currently HIV/AIDS-defining infections, yet may be seen by practicing pathologists.     

Allopurinol hypersensitivity syndrome: hypersensitivity to oxypurinol but not allopurinol

OBJECTIVE: We assessed the clinical, histological, and virological features of anogenital human papillomavirus (HPV) infection, according to their immune status in HIV-1 infected men, referred for an anogenital examination or treatment, in comparison with immunocompetent patients. METHODS: The study population comprised 33 HIV-1 infected heterosexual or homosexual men and 38 HIV negative men seen in a screening and treatment centre for anogenital HPV infections. All patients were examined with a colposcope. Biopsies were carried out on all subjects with anogenital lesions for histological studies and HPV detection by Southern blot. RESULTS: The HIV infected patients had a balanopreputial HPV infection in 70%, anal in 30%, and urethral in 37%, while HIV negative patients had balanopreputial lesion in 72%, anal in 26%, and urethral in 16%. Diffuse anogenital lesions were present in 33% of the HIV infected cases and in 10.5% of HIV negative cases (p < 0.02). Among the HIV infected patients, the genital HPV lesions were condylomatous in 67.5% of the cases and dysplastic in 57%. HIV negative patients had condylomatous lesions in 86% of the cases and dysplasic in 14%. The condylomatous lesions of HIV infected patients had a low grade malignant histological aspect in 36% of the cases and high grade histological criteria were found in 22% of the dysplasias. Oncogenic HPVs were detected more frequently in HIV infected patients (35% v 12%) and more than one HPV type was found in 21.5% of cases. Neither the anogenital diffusion of the HPV lesions nor their morphological, histological, and virological features differed significantly in patient with CD4 cell counts > or < 200 x 10(6)/l. In contrast, patients with CD4 cell counts < 50 x 10(6)/l had a higher risk of several types of HPVs and of developing a diffuse anogenital infection. CONCLUSION: HIV-1 infected patients had an increased frequency of high grade anogenital dysplastic lesions and a higher frequency of HPV infection with multiple and diffuse sites of involvement. These characteristics of HPV infection were independent of the patients' immune status up to CD4 cell counts > 50 x 10(6)/l but showed an increased risk when the CD4 cell count was < 50 x 10(6)/l. The higher frequency of diffuse anogenital infections among HIV infected men calls for rapid treatment, laser or surgery, given the association of histological features of intraepithelial neoplasia and the presence of multiple HPV infection sites which may be the consequence of immune disturbances, most of which are transmissible potentially oncogenic HPVs.     

Dermatologic complications of HIV infection

Cutaneous disorders occur with great frequency in patients with HIV infection and increase in number and severity as the disease progresses and immune function declines. In addition, the first findings related to HIV infection are often on the skin. Cutaneous infections with herpesviruses may be severe and atypical in their presentations; papillomaviruses and MC are common as well. Bacterial infections may be primary or secondary to other skin diseases; superficial and deep fungal infections are also prevalent. Papulosquamous disorders, including seborrheic dermatitis, psoriasis, and eczema, may be disfiguring and result in secondary complications. Neoplastic disorders, especially Kaposi's sarcoma, demand early diagnosis, to afford the patient maximal treatment options. All physicians must be aware of these cutaneous manifestations to decrease morbidity and improve quality of life in the HIV-infected individual.     

Protease inhibitors in patients with HIV disease. Clinically important pharmacokinetic considerations

Since its introduction in 1987, zidovudine monotherapy has been the treatment of choice for patients with HIV infection. Unfortunately it has been established that the beneficial effects of zidovudine are not sustained due to the development of resistant viral strains. This has led to the strategy of combination therapy, and in 1995 treatment with zidovudine plus didanosine, or zidovudine plus zalcitabine, was demonstrated to be more effective than zidovudine monotherapy in preventing disease progression and reducing mortality in patients with HIV disease. Recent work demonstrates an even greater antiviral effect from triple therapy with 2 nucleosides, zidovudine plus zalcitabine with the addition of saquinavir, a new protease inhibitor drug. The HIV protease enzyme is responsible for the post-translational processing of gag and gag-pol polyprotein precursors, and its inhibition by drugs such as saquinavir, ritonavir, indinavir and VX-478 results in the production of non-infectious virions. As resistance may also develop to the protease inhibitors they may be used in combination, and future strategies may well include quadruple therapy with 2 nucleoside analogues plus 2 protease inhibitors. Administration of protease inhibitors alone or in combination with other drugs does raise a number of important pharmacokinetic issues for patients with HIV disease. Some protease inhibitors (e.g. saquinavir) have kinetic profiles characterised by reduced absorption and a high first pass effect, resulting in poor bioavailability which may be improved by administrating with food. Physiological factors including achlorhydria, malabsorption and hepatic dysfunction may influence the bioavailability of protease inhibitors in HIV disease. Protease inhibitors are very highly bound to plasma proteins (> 98%), predominantly to alpha 1-acid glycoprotein. This may influence their antiviral activity in vitro and may also predispose to plasma protein displacement interactions. Such interactions are usually only of clinical relevance if the metabolism of the displaced drug is also inhibited. This is precisely the situation likely to pertain to the protease inhibitors, as ritonavir may displace other protease inhibitor drugs, such as saquinavir, from plasma proteins and inhibit their metabolism. Protease inhibitors are extensively metabolised by the cytochrome P450 (CYP) enzymes present in the liver and small intestine. In vitro studies suggest that the most influential CYP isoenzyme involved in the metabolism of the protease inhibitors is CYP3A, with the isoforms CYP2C9 and CYP2D6 also contributing. Ritonavir has an elimination half-life (t1/2 beta) of 3 hours, indinavir 2 hours and saquinavir between 7 and 12 hours. Renal elimination is not significant, with less than 5% of ritonavir and saquinavir excreted in the unchanged form. As patients with HIV disease are likely to be taking multiple prolonged drug regimens this may lead to drug interactions as a result of enzyme induction or inhibition. Recognised enzyme inducers of CYP3A, which are likely to be prescribed for patients with HIV disease, include rifampicin (rifampin) [treatment of pulmonary tuberculosis], rifabutin (treatment and prophylaxis of Mycobacterium avium complex), phenobarbital (phenobarbitone), phenytoin and carbamazepine (treatment of seizures secondary to cerebral toxoplasmosis or cerebral lymphoma). These drugs may reduce the plasma concentrations of the protease inhibitors and reduce their antiviral efficacy. If coadministered drugs are substrates for a common CYP enzyme, the elimination of one or both drugs may be impaired. Drugs which are metabolised by CYP3A and are likely to be used in the treatment of patients with HIV disease include the azole antifungals, macrolide antibiotics and dapsone; therefore, protease inhibitors may interact with these drugs. (ABSTRACT TRUNCATED)     

The course of preexistent immune abnormalities in HIV negative haemophiliacs treated for two years with a monoclonal purified factor VIII concentrate

The administration of factor VIII concentrates has been associated with immune abnormalities in patients with severe haemophilia A, even in the absence of HIV infection. The effects of a monoclonal purified factor VIII concentrate, Hemofil M (Baxter), on preexistent immune abnormalities were assessed over a 2 year period in 22 HIV negative haemophiliacs. They were treated previously with other concentrates, and received Hemofil T from 1983 to 1988. No HIV infection was demonstrated. No serologic evidence for other viral (re)-infections was seen. A decrease of HLA-DR expression on non-B lymphocytes in the first year (P = 0.026), and a decrease of T4-T8 ratio over the 2 years were found (P = 0.0016). Skin tests were non-contributive. The decrease in HLA-DR expression is suggestive for an improved immune function, possibly due to a reduced content of protein or virus in this concentrate.     

HLA-derived peptides as novel immunosuppressives

Over the past decade the use of synthetic peptides corresponding to linear sequences of HLA molecules has progressed from a concept to a reality. These peptides are currently being evaluated in clinical trials. In animal models these peptides, given over 1 week with cyclosporin alone, induced long-term immunological tolerance (Figure 3). They may similarly induce tolerance in humans. The next major hurdle for such tolerogenic drugs, however, is to prove efficacy in clinical circumstances. Many of the drugs used to treat transplant patients today (steroids, cyclosporin, azathioprine, mycophenolate mofetil) may actually inhibit the 'active' processes of induction and maintenance of immunological tolerance. Demonstration that new drugs induce tolerance will require efficacy studies in other immune-mediated diseases in which monotherapy is feasible (such as psoriasis), before further advances can be made in the induction of transplant tolerance. In addition, rapid assays of rejection must be developed in order to reverse tolerance induction failures without graft damage or loss. Lastly, it will require heroic physicians, surgeons, and patients to make immunological tolerance a reproducible clinical reality.